MALARIA 



MALARIA 

ETIOLOGY, PATHOLOGY, DIAGNOSIS, 
PROPHYLAXIS, AND TREATMENT 



BY 

GRAHAM E. HENSON, M. D. 

MEMBER AMERICAN MEDICAL ASSOCIATION, FLORIDA MEDICAL ASSOCIATION, SOUTHERN 

MEDICAL ASSOCIATION, AMERICAN SOCIETY OF TROPICAL MEDICINE, MEDICAL 

RESERVE CORPS, UNITED STATES ARMY (NON-ACTIVE LIST) 



WITH AN INTRODUCTION BY 

CHARLES C. BASS, M. D. 

PROFESSOR OF EXPERIMENTAL MEDICINE, MEDICAL DEPARTMENT 
TULANE UNIVERSITY, NEAV ORLEANS 



TWENTY-SEVEN ILLUSTRATIONS 



ST. LOUIS 

C. V. MOSBY COMPANY 

1913 



~R C I 5 Co 

M 4- 



Copyright, 1913, by C. V. Mosby Company 



Press of 

C. V. Mosby Company 

St. Louis 



©CI.A350910 
*-0/ 



TO MY FRIEND AND CONFRERE 
JAMES WOOFFENDALE INCHES, M.D., 

WHO, BY MANY ACTS OF KINDNESS AND 

WORDS OF ENCOURAGEMENT, DID MUCH 

TO ASSIST ME IN MY STUDENT DAYS 

AND EARLY PROFESSIONAL CAREER 

THESE PAGES ARE AFFECTIONATELY 
DEDICATED BY THE AUTHOR 



PREFACE. 

There is little doubt that the eradication of malaria is the most 
serious problem that confronts the sanitarian in all tropical and 
sub-tropical countries. The completion of the Panama Canal will 
forever be a monument to progressive sanitation which the Amer- 
ican people may point to with pride. Under the splendid general- 
ship of Colonel W. C. Gorgas, malaria and other tropical diseases 
have been successfully coped with, some to the point of complete 
eradication, others to such an extent as not to seriously interfere 
with the mechanical work incident to the building of the Canal. 
The most important disease in the latter category is malaria. 

It is doubtful if there is any disease as easy to diagnosticate as 
malaria, if proper attention be paid to diagnostic methods, or if 
there is any that responds as surely to treatment, if proper treat- 
ment be instituted ; for it must be remembered that quinin is one 
of a very few therapeutic specifics in our possession. 

The author believes that one of the most sacred duties the gen- 
eral practitioner in malarial regions owes to the community in 
which he lives, is his assistance in the eradication of malaria, and 
inasmuch as he considers that one of the most if not the most im- 
portant prophylactic unit to be the early recognition and proper 
treatment of the disease, especial attention has been given in the 
following pages to diagnosis and treatment. 

It has been with the view of presenting the subject in a practical 
manner that this work has been written, and it is the earnest hope 
of the writer that he has not entirely failed in doing this. 

The literature has been carefully reviewed and the author has 
not hesitated to make extensive quotations where he considered they 
were of especial value ; in every instance proper recognition has 
been given the original author — if there are any exceptions it has 
been through error. 

The author wishes especially to acknowledge his indebtedness 
to the writings of Sir Ronald Ross, Doctor Charles F. Craig, and 
Doctor William H. Deaderick. He wishes to express thanks to 
Doctor Craig for the use of many of the photomicrographs used 



PREFACE. 

in illustrating the text, and for other courtesies; to Doctor Joseph 
Y. Porter for the cuts illustrating the various species of mosquitoes; 
to Doctor Hiram Byrd for many valuable suggestions in the prep- 
aration of the manuscript, and to others who have in many ways 
been of assistance in the preparation of this work. 

G. E. H. 
Jacksonville, Fla., June, 1913. 



CONTENTS. 



CHAPTER I. 
GENERAL CONSIDERATIONS. 

PAGE 

Definition — Historical — Geographical Distribution — Economic Loss . 17 

CHAPTER II. 
ETIOLOGY — THE MALARIAL PARASITES. 

Classification of the Malarial Parasites — Schizogony — Formation of 
Gametes — Sporogony — Description of the Malarial Plasmodia — 
Staining Reactions of the Plasmodia — Description of Gametes and 
Staining Qualities 26 

CHAPTER III. 

ETIOLOGY — THE MALARIA-CARRYING MOSQUITOES. 

Habits of the Anophelines — General Description of the Anophelines — 

Development of the Malarial Plasmodia in the Mosquito .... 51 

CHAPTER IV. 

ETIOLOGY — OTHER FACTORS. 

Predisposing Factors — Congenital Malaria — Pathogenesis — Period of 
Incubation — Factor in Intense Infections — Immunity — Endemic In- 
dex — Old-Time Theories Concerning Transmission — Cultivation of 
Malarial Plasmodia — Factors Determining the Amount of Malaria 
in a Given Community 61 

CHAPTER V. 

PATHOLOGY — COMPLICATIONS — SEQUELAE — PROGNOSIS. 

Pathology — Complications — Sequelae — Prognosis 79 

CHAPTER VI. 

DIAGNOSIS. 

Clinical Diagnosis — Laboratory Diagnosis — Differential Diagnosis — 

Symptomatology — Fstivo-Autumnal Infections — Pernicious Fevers 91 

CHAPTER VII. 

LATENCY — RECURRENCES — CHRONICITY. 

Latent Malaria — Etiology of Malarial Recurrences — Significance of Re- 
curring Infections — Frequency of Recurrences — Masked Malaria — 
Chronic Malarial Cachexia 121 



CONTENTS 

CHAPTER VIII. 
PROPHYLAXIS. 

PAGE 

Measures Directed Against the Plasmodia — Measures Directed Against the 
Mosquito — Mechanical Means to Prevent the Mosquito from Gaining 
Access to Man — Public Education on all Measures for the Control and 
Prevention of Malaria 134 



CHAPTER IX. 
TREATMENT. 

History of Quinin — Action of Quinin — Choice of Preparation of Quinin 

— Time and Amount of Administration of Quinin — Methods of Ad- 
ministration of Quinin — Other Methods of Treatment — General 
Management of Acute Malaria, and Treatment of Special Symptoms 

— Treatment of Malaria in the Pregnant Woman — Treatment of 
Pernicious Fevers — Treatment of Chronic Malarial Cachexia . . 152 



ILLUSTRATIONS. 

FIG. PAGE 

1 Plasmodium vivax (Tertian plasmodium) . Young ring forms . . 33 

2 Plasmodium vivax (Tertian plasmodium). Half-grown parasite. 

(After Craig) 33 

3. Plasmodium vivax (Tertian plasmodium). Presegmenting parasite. 

(After Craig) 34 

4 Plasmodium vivax (Tertian plasmodium). Segmenting tertian para- 

site. (After Craig) 34 

5 Plasmodium vivax (Tertian plasmodium). Total separation of the 

spores. (After Craig) 35 

6 Plasmodium Malaria? (Quartan plasmodium). One quarter-grown 

parasite. (After Craig) 37 

7 Plasmodium Malarise (Quartan plasmodium). Presegmenting para- 

site. (After Craig) 38 

8 Plasmodium Malaria? (Quartan plasmodium). Segmenting parasite. 

(After Craig) 38 

9 Plasmodium falciparum (Tertian estivo-autumnal plasmodium). 

Multiple invasion with the estivo-autumnal parasite . . . .39 

10 Plasmodium falciparum (Tertian estivo-autumnal plasmodium). 

Young ring forms. (After Craig) 39 

1 1 Plasmodium falciparum ( Tertian estivo-autumnal plasmodium ) . 

Segmenting form of the parasite. (After Craig) 40 

12 Plasmodium Malaria? (Quartan plasmodium). Band form of the 

parasite. (After Craig) 45 

13 Plasmodium falciparum (Tertian estivo-autumnal plasmodium). Fe- 

male crescent. Macrogamete. (After Craig) 48 

14 Plasmodium falciparum (Tertian estivo-autumnal plasmodium). 

Male crescent. Microgametocyte. (After Craig) 49 

15 Resting position of Anopheles maculipennis, Meigen; enlarged. (After 

Howard) 53 

16 Resting position of Anopheles and Culex. (After Howard; from 

sketch by Waterhouse) 53 

17 Anopheles argyrotarsis, Desvoidy; adult female, enlarged. (After 

Howard) 54 

18 Female of Anopheles punctipennis, Say; enlarged. (After Howard) 55 

19 Male of Anopheles punctipennis, Say; from side; enlarged. (After 

Howard) 56 



ILLUSTRATIONS 

FIG. PAGE 

20 Anopheles crucians, Wiedemann ; adult female ; enlarged. The most 

common species found in the southern states. (After Howard) . 57 

21 Male and female of Anopheles maculipennis, Meigen, (After Howard) 58 

22 Preparation of blood smear, the size of blood drop, and angle at which 

the slide is held 99 

23 The contact slide, the blood running to the edges of the specimen 

slide by capillary attraction 100 

24 The contact slide having been passed rapidly upward over specimen 

slide, a thin even smear resulting 101 

25 A typical breeding place for anopheles mosquitoes 138 

26 Large drainage scheme, acting in double capacity of removing mos- 

quito breeding places, and rendering land suitable for agricultural 
purposes 139 

27 A modest dwelling with efficient protection against malarial infection 146 



GLOSSARY 



Anopheles, a genus of the 
sub-family Anophelinae, all of 
which are capable of transmit- 
ting malaria. 

Anophelinae, sub-family of 
mosquitoes, certain of which are 
capable of transmitting ma- 
leria. 

Asexual cycle, the cycle of 
the malaria parasite occurring 
in man. 

Crescents, the sexual forms 
of the malarial parasite seen 
in the estivo-autumnal infec- 
tions. 

Flagella, the male sexual 
forms. 

Gametes, sexual forms of the 
parasite. 

Halteridium, the parasite of 
malaria occurring in birds. 

Human cycle, the cycle of 
the malarial parasite occurring 
in man. 

Macrogametes, the female 
sexual forms. 

Merozoites, the organisms 
resulting from the sporulation 
of the Schizont. 

Microgametes, same as fla- 
gella. 

Microgametocyte, a 
gametocvte. 



male 



Mosquito cycle, the cycle of 
the malarial parasite occur- 
ring in the mosquito. 



Oocyst, the organism evolv- 
ing from the ookinete. 

Ookinete, the organism evolv- 
ing from the fertilized macrog- 
amete. 

Parthenogenesis, reproduc- 
tion without fertilization. 

Schizogony, the evolution of 
the parasite in man. 

Schizonts, the asexual forms 
of the parasite. 

Sexual cycle, the cycle of the 
malarial parasite occurring in 
the mosquito. 

Sporoblasts, spherical bodies 
seen in the oocyst, finally evolv- 
ing to sporozoites. 

Sporogentic forms, the vari- 
ous forms seen during the cycle 
of the parasite in the mosquito. 

Sporogony, the evolution of 
the parasite in the mosquito. 

Sporonts, same as oocyst. 

Sporozoites, small organisms 
the final product of sporogony 
with which mosquitoes transmit 
malaria to man. 

Sporozoa, the class of para- 
sitic protozoa including the 
malarial parasites. 

Trophozoite, the young form 
of the parasite seen after the 
merozoite enters the red cells. 

Zygote, same as ookinete. 



INTRODUCTION. 

BY CHARLES C. BASS, M. D., NEW ORLEANS. 

It gives me great pleasure to write a short note of approval and 
commendation of this book after carefully reading the proof. 
Malaria is just at this time attracting special attention of the med- 
ical profession and of others. Other countries are taking up seri- 
ously the eradication of the disease. Its prevalence to the present 
extent is a discredit to the intelligence and progressiveness of the 
American people. There are indeed few diseases which could be 
so easily prevented and for which we have so perfect a specific. 
Every year the South pays her tribute of thousands of lives to this 
preventable and curable disease, to say nothing of the suffering, 
inefficiency and loss of millions in wealth. The development of this 
great section of the country has been held in check mainly by three 
diseases — yellow fever, which broke out at intervals, setting the 
whole country in panic, and leading to that destroyer of commerce, 
shotgun quarantine; hookworm disease, which insiduously sapped 
the very life-blood of millions of the youth of the country ; and 
malaria, which perhaps takes greater toll than either. Through a 
clear understanding of the disease, yellow fever has gone, never to 
return in epidemic form. Hookworm disease is rapidly being 
eradicated by the combined efforts of the State Boards of Health, 
the Rockefeller Hookworm Commission, and the medical profes- 
sion. But malaria continues little checked mainly for lack of suf- 
ficient knowledge on a subject as simple perhaps as either yellow 
fever or hookworm disease. 

The appearance, therefore, of this work at this time is indeed 
fortunate. It is written for the general practitioner by a man 
whose experience and research in this disease for many years in 
one of the most intensely malarious sections of the United States 
enables him to view the subject from the most practical standpoint. 



MALARIA. 



CHAPTER I. 

GENERAL CONSIDERATIONS. 

DEFINITION. 

Malarial fever is a disease produced by specific organisms, be- 
longing to the class Sporozoa, genus Plasmodium, which penetrate 
and occupy the red corpuscles, destroying those they occupy, and 
producing an anemia, which is accompanied by an enlargement of 
the spleen and other pathologic lesions. The disease is character- 
ized by a periodicity in its clinical symptoms concomitant with the 
sporulation of the organisms which occurs at definite intervals, 
depending on the species of plasmodia, these being the benign 
tertian, the quartan, the estivo-autumnal tertian, and the estivo- 
autumnal quotidian, all of which can be differentiated by vari- 
ations in their morphology. The fever accompanying the invasion 
may be remittent, intermittent, or continuous, and may or may 
not be preceded by chills or followed by intense sweating. The 
disease is transmitted by certain mosquitoes belonging to the 
AnophelinaB group and can be contracted in no other way. All 
forms of the disease, in all of its stages respond to the quinin salts 
if properly administered. 

HISTORICAL. 

The disease was given its name by Torti, who, in 1753 A.D., 
wrote a very thorough and exhaustive work on the subject, in 
which he classified the various forms. It was given the name 
mal aria, meaning bad air, in view of the popular idea that the 
infection was contracted by inhaling miasmatic odors common 
around swamps and marshlands. 

The history of the infection is a complete one and has its begin- 
ning at a period even antedating the Christian era. Deaderick 
states that the disease is mentioned in the Orphic poems, both the 
quartan and tertian types being alluded to, this a thousand years 
before Christ. Hippocrates wrote on periodic fevers, dividing 

17 



18 MALARIA. 

them into quotidian, tertian, subtertian, and quartan. Galen, 
Cicero, Varro, Levy, and Celsus also described periodic fevers, and 
in the days of the Roman Empire when the ravages of the disease 
were at a very high point, there were extensive drainage schemes, 
as described by Celli, consisting of large aqueducts, showing that 
the sanitarians of those days were upon the right track, even 
if they were largely working in the dark. Craig in speaking of 
this work considers, as evidence of the success of these operations, 
the fact that districts then having populous and thriving cities, 
since gone to ruin, are now uninhabitable as a result of the per- 
nicious forms of malaria that prevail. It is impossible to say, 
however, to what extent malaria may itself be responsible for the 
very existence of these ruins, for it has often been claimed that 
the fall of the Roman Empire was in certain measures due to the 
undermining influences of this disease. 

Leaving behind us the Middle Ages, noted for its days of dark- 
ness and superstition and all that such implies, and during which, 
as might be expected, little if any knowledge was attained con- 
cerning the disease, we come to the year 1640 in which the Countess 
Chinchon introduced cinchona into Europe. This drug was origi- 
nally studied by La Condamine in the province of Loxa, and named 
by him "quinquina" in the year 1737, and in 1741 Linne proposed 
a new name, "cinchona," in honor of the woman who had intro- 
duced it. The use of this drug, which has since proved a specific 
in malarial fevers, was bitterly opposed for many years by certain 
religious bodies, and in Rome, a veritable hotbed of malaria, it 
was not used until nine years after its introduction, at which time 
the Jesuits began to use it extensively. Following the introduc- 
tion of quinin we find a slow but steady advancement in knowledge 
concerning the disease. Morton had, in 1697, described the simple 
and pernicious forms and was enthusiastic in his support of treat- 
ment with cinchona. Lancasi, in 1717, suggested that the infection 
may be transmitted by mosquitoes, being probably the first to ex- 
press such an opinion. Torti, in 1753, in his paper already referred 
to, gave an exhaustive description and classification of its various 
forms. Meckel, in 1847, was the first to describe the pigmented 
leucocytes, a familiar picture now in the study of malarial blood. 
In 1849, Mitchell's theory that certain spores existing in marsh- 
lands are the etiological factor received much credence, and 
secured increased favor when Salisbury, in 1866, connected the 



GENERAL CONSIDERATIONS. 19 

spores of Palmella with the etiology. These spores he found in 
numerous quantities on the banks of the Ohio and Mississippi 
rivers, and he thought at the time that he was able to demonstrate 
them in the urine of patients suffering with malaria. "When Klebs 
rind Tommasi Crudeli, in 1879, announced the discovery of what 
they named the Bacillus malaria, which they found in the mud of 
marshy districts wherever malaria was rampant, and were able to 
reproduce them by culture methods, producing the symptoms of 
a malarial infection when injected into man's circulation, it was 
generally considered by the medical world that at last the organism 
causing the infection was isolated. 

The following year Laveran, an army surgeon in the French 
Service, announced, through the Academy of Medicine in Paris, 
the discovery of parasites in the blood of people suffering from 
malaria. This announcement marked an epoch in the history of 
the disease and was an event of the greatest importance occurring 
in medical circles for generations. His descriptions covered the 
crescentic forms of the estivo-autumnal infections and also the 
flagellated forms, which were described by him as being hyaline 
bodies containing much pigment, and from which protruded hyaline 
filaments which gave to the organism ameboid movement ; it was 
this form of the parasite that put beyond any doubt in his mind 
the fact that they were true parasites — to quote his own words : 
"From then on I had no further doubt as to the parasitic nature 
of these elements which I had found in the blood. ' ' His announce- 
ment, which was followed a year later by a more extended report, 
did not meet with the consideration that such an important dis- 
covery merited, and it was not until the year 1885 that much at- 
tention was paid to his words. In 1882 Richard, a confrere of 
Laveran in the French Army Service, confirmed the discovery and 
described the young ring forms of the parasite, and, in 1885, 
Marchiafava and Celli came forward and also confirmed Laveran 's 
original findings. The confirmation by these authorities resulted 
in much scientific interest, for these two men, whose opinions Avere 
highly held, had until that time strongly upheld the theory of 
Klebs and Tommasi Crudeli that the origin of the disease is 
bacterial in nature. The following year the true nature of the 
malarial organisms was definitely established and accepted through- 
out the medical world, many observers confirming the findings of 
Laveran. In the same year Golgi associated the periodicity of the 



20 MALARIA. 

fevers with the sporulation of the parasites, and this has since 
been confirmed by Osier and many others. Later work, which 
will not be discussed here in detail, resulted in a complete knowledge 
of the morphology and biology of the various parasites throughout 
the cycle both in man and in the- mosquito. 

This discovery of Laveran made possible the diagnosis of malaria 
from other fevers by more certain and satisfactory methods than 
the mere fact of a fever's responding or failing to respond to the 
action of the quinin salts, and attention was now directed to the 
mode of transmission. The theory of insect transmission had at 
various times been suggested, but no definite investigation had been 
carried on. During more recent years King in 1883, Koch in 1884, 
Laveran in 1884, Fliigge in 1891, Manson in 1894, and Bignami 
in 1896 had all advanced and supported the theory. 1 But it was the 
hypothesis of Manson, advanced in his Goulstonian lectures, and 
his direct suggestion, that was responsible for Ross, in 1895, 
going into research work to establish it as a fact. His work, which 
was most painstaking and thorough, aroused for him the admiration 
of the scientific world and resulted in his being able to demonstrate 
beyond all doubt that certain mosquitoes are necessary for the 
transmission of the parasite; that these insects act as the inter- 
mediary host, allowing certain processes of evolution to take place ; 
and that the body of the insect is the natural habitat for the 
development of this evolution which can take place in no other 
way. 

In 1898, MacCallum completed the chain of knowledge that had 
taken all these years to accumulate, and by his studies and observa- 
tions of the sexual forms of the parasite determined that the flagel- 
lated forms become detached from the parent body and penetrate 
the female organism, resulting in its fertilization. After study- 
ing this process in the Anopheles, he . determined that it takes 
place in the stomach of the insect, and is analogous to the cycle 
taking place in the Gulex with the Halteridium. His observations 
have since been confirmed by numerous observers. 

Bignami, in 1898, was the first to produce the disease by inocu- 
lating a person with no previous history of malaria. This was 
followed by numerous inoculations from mosquito to man. In 
1899, Bastianelli, Bignami, and Grassi infected mosquitoes with 

1 It may be mentioned in passing, as an interesting: historical fact, that at this junc- 
ture Smith and Kilborne, of the Bureau of Animal Industry, Washington, established the 
fact that Texas fever in cattle is transmitted by ticks. 



GENERAL CONSIDERATIONS. 21 

the gametes of a quartan infection, and followed the evolution of 
these forms to that of the sporozoite. 

The detailed story of the discovery of Ross that the mosquito is 
the transmitting agency, how it was later demonstrated in various 
ways, such as a number of people living in the Roman Campagna in 
exactly the same manner as the natives, with the single exception 
of adequate mosquito protection, thereby saving themselves from 
infection, while the unprotected natives all became sick; how 
Manson further demonstrated the correctness of the theory by im- 
porting from Italy infected mosquitoes and producing the infection 
in his own son and another gentleman in London ; and various 
other experiments, together with the investigations carried on by 
many observers concerning the life cycle of the parasites in the 
mosquito, have brought the question of transmission to a point of 
accepted fact. The application of this knowledge in the extensive 
work done in Panama, and other points, in the eradication of 
malaria, completes the history of the disease. 

GEOGRAPHICAL DISTRIBUTION. 

Malaria while classified as a tropical disease is by no means one 
that is confined to tropical or subtropical countries. The method 
of transmission is such that conditions necessary for its propa- 
gation are prevalent to a greater degree in the warm climates than 
in the cooler ones. The disease prevails on every one of the conti- 
nents, increasing in extent and severity as the warmer portions are 
reached ; but while the estivo-autumnal and quartan infections are- 
more closely confined to warmer latitudes in both hemispheres, 
this being more especially marked of the estivo-autumnal than of 
the quartan type, the benign tertian infection can be seen in almost 
any latitude below 60 degrees. 

North America. — In North America the disease is endemic in cer-, 
tain portions of all of the Southern states, those known as the Gulf 
states being especially badly infected. The estivo-autumnal tertian 
variety is very common in certain parts of Florida, and the quo- 
tidian form is present, but not so often encountered. The author 
has known as high as 80 per cent of the population in certain 
portions of this state to become infected in a single season, while 
Hie disease is endemic to the point that, in certain localities at 
least, 25 per cent are annually attacked. Georgia, Texas, and 
certain parts of South Carolina are also heavily infected with both 



22 MALARIA. 

the estivo-autumnal and benign tertian types. Along the Missis- 
sippi River toward its southern course estivo-autumnal malaria is 
very prevalent and especially severe, resulting in many fatalities. 
The disease is quite common in Missouri, Oklahoma, Arkansas, and 
Kansas; present, but less frequent, in North Carolina, Virginia, 
West Virginia, and Maryland. In the New England states the 
tertian infection is very often seen, but the more severe forms are 
seldom encountered ; while in the Middle Western states the tertian 
variety is often observed, and occasionally estivo-autumnal types 
occur. A few years ago the latter was reported quite prevalent 
in certain portions of Indiana, and there are sections of Michigan, 
Ohio, Illinois, Minnesota, and Wisconsin that still have tertian 
malaria of the benign form to deal with. Passing through the 
Western states and approaching the Pacific Coast, the disease be- 
comes less frequent, but it is more or less prevalent in Washington 
along the Puget Sound and Columbia River. Portions of Oregon 
remain infected, and in some parts of the state of California all 
forms of the disease are frequently seen. Canada is practically 
exempt, with the exception of that part of her southern border 
touching on the Great Lakes. 

Mexico and Central America are badly infected, and the disease 
has numbered its victims by thousands. Panama, especially 
severely infected with the estivo-autumnal types in the past, is now 
enjoying the benefits of a continued campaign in that portion 
known as the Canal Zone, where active measures against 
the mosquito, together with protection afforded the employees by 
screening and the prophylactic use of quinin, has resulted in a 
very marked reduction in both mortality and morbidity from this 
cause, together with a general improvement of health conditions, 
showing to the world in a striking manner what can be accomplished 
under even the most unfavorable conditions where proper measures 
are consistently carried out, 

South America. — AH of South America is severely infected to a 
greater or lesser degree, some portions being uninhabitable on ac- 
count of the malignancy of the infections. Peru, the Argentine 
Republic, and Uruguay are exceptions to the rest of the continent, 
the infection in these countries in any of its forms being rather 
rare. 

West Indies. — The West Indies still harbor the disease to a point 
of great severity both in its prevalence and in its malignancy, tak- 



GENERAL CONSIDERATIONS. 23 

ing on its most dangerous forms in Cuba. Porto Rico is nearly 
free from the severe types, the benign tertian being the form 
generally seen ; while St. Vincent and the Barbadoes are said to be 
practically free from any of the malarial infections. 

Europe. — At one time Great Britain was quite severely infected, 
but the disease is now extinct, in spite of the fact that Anopheles 
are present. This phenomenon has been quite generally discussed 
by modern writers ; Manson suggested the possibility of the insects 
feeding on some vegetable juice poisonous to the parasites, while 
Samson considered the possibility of the existence of hyperparatism : 
that is, the presence of some other organism that destroys or in- 
terferes with the development of the malarial parasite in the body 
cf the mosquito. It is, howeA T er, more than probable that the 
extinction has gradually been brought about by the reduction of 
gamete carriers among the inhabitants of those islands, together 
with the fact that although Anopheles are present they are not in 
great numbers. 

On the European continent malaria is widely distributed. 
France, Germany, Holland, Belgium, Spain, and Portugal are all 
more or less severely infected with the benign tertian, while Italy, 
Greece, Sicily, and Turkey have suffered from the ravages of the 
disease to a maximum for many centuries, all forms of the disease 
being present. In Sweden and Denmark occasional cases are seen, 
but Norway is practically exempt. 

Asia. — Asia presents many zones of infection, India being very 
severely infected, the disease costing the English government an 
immense sum annually, and the country a death toll of a million 
lives in what they term an ordinary malarial year, while there are 
some years during which an exacerbation of the disease results in 
four or five million deaths. The infections are also seen in the low- 
lands of Japan, and in the Philippine Islands they are especially 
severe, the estivo-autumnal types being very prevalent, In the 
years 1900-1901, along the Cauayan River, in the upper part of the 
province of Luzon, fully 50 per cent of our military force was in- 
fected, many fatalities occurring. 

Africa. — On the west coast of Africa the most intense infections 
are seen, and the malignant types are common along the Congo and 
Nile rivers. The islands of Madagascar and Mauritius are also 
badly infected. 

Australia.— The disease occurs along the entire coast of 



24 MALARIA. 

Australia, but the interior of the country is comparatively free. 
It is seen by the above review of the geographical distribution 
that malaria covers practically the entire surface of the globe. 
It has been claimed that it has reappeared in America of late years 
as the result of troops returning with the infection contracted while 
serving on our island dependencies, in sections where it had become 
practically unknown. Craig cites an instance occurring in a 
city in Connecticut, where some years before the Spanish-American 
war occasional cases of benign tertian malaria only were observed. 
Following the return to tfris city of a company of militia, several 
residents, who had not been away, developed estivo-autumnal 
malaria, which was traced to the returning soldiers, several of 
whom had suffered with such attacks while serving in Cuba ; and 
this illustrates how an infection of this nature can develop follow- 
ing the importation of gamete carriers. The Anopheles were 
present all the time, some few carriers of the benign tertian gametes 
kept that infection alive, but during a period of many years no 
eases of estivo-autumnal infections had occurred until this type 
was introduced following the return of these soldiers, some of whom 
harbored the crescentic forms. 

ECONOMIC LOSS. 

An estimation of the immense loss attributable to malaria through- 
out the world is impossible of anything even approaching accuracy, 
but we can gather enough to show that every possible effort should 
be put forth against a disease that is so easily within our power 
to eradicate. 

Celli shows that the economic loss to Italy has been an enormous 
one. In addition to that incurred as a direct result of malarial in- 
fections, he claims that the existence of the disease has been respon- 
sible for large tracts of land remaining uncultivated, owing to the 
fact that the territory was uninhabitable on account of the prev- 
alence and the intensity of the malarial infections. He sums up 
the situation with the statement that "Malaria annually costs Italy 
incalculable treasure. ' ' 

Leslie estimates the mortality in India from this cause at 1,130,000 
annually "in an ordinary malarial year — and as in such a year 
it is not a very fatal disease, this number of deaths represents an 
enormous amount of suffering and loss of labor, often at a time 
when labor is of most value. ' ' 



GENERAL CONSIDERATIONS. 25 

Ricchi calculates that the Adriatic Railway Company alone, for 
1,400 kilometers of railway and for 6,416 workmen in the malarial 
zones, spends on account of malaria the enormous sum of 1,050,000 
francs a year. 

Taking as an estimate the number of deaths attributable to ma- 
laria in the registration area of the United States, which has for the 
past many years exceeded a thousand, admitting a mortality rate 
of one per cent (which is high), we can account for a hundred 
thousand cases annually; and when we take into consideration the 
fact that these figures do not include the rural population and only 
a very small proportion of the city populations of the Southern 
states (these not being represented in the registration area, owing 
to inefficient regulations concerning the recording of their vital 
statistics), and that it is in this portion of our country that most 
of our malaria prevails, it can be seen at a glance what, even at 
this day, malaria means to the American people. The loss of time 
to the wage-earner, the care of the sick, and the necessary expendi- 
tures for medical attendance and drugs will run the total into 
millions of dollars every year, and Howard has even estimated this 
total as being $100,000,00.0 annually. 

With such figures before us, and the knowledge we have of what 
has been accomplished wherever a consistent campaign has been 
instituted against the malarial infections, it would appear that the 
time cannot be far distant when the matter of the eradication of the 
disease will be taken up seriously by legislative and administrative 
bodies. 



CHAPTER II. 
ETIOLOGY— THE MALARIAL PARASITES. 

With Laveran's discovery that the disease is produced by spe-i 
cific organisms, Manson's and Ross' work showing conclusively that 
these organisms are carried and injected into the human circu- 
lation by certain forms of mosquitoes, MacCallum's elucidation of 
the significance of the gametes in the circulation of man, and the 
later role enacted by them in the body of the mosquito, it is 
definitely established that two requisites exist in every malarial 
district, each harmless in the spreading of the disease without the 
aid of the other. These are: (1) certain mosquitoes, members of 
the Anophelinas group ; and ( 2 ) man, who may or may not have 
had acute clinical manifestations of the disease, but who harbors 
in his circulation the sexual forms of the parasite. The mosquito 
cannot originate or produce an infection, but must first become in- 
fected itself, by feeding on the blood of man whose blood contains 
the sexual forms of the parasite. The sexual cycle cannot proceed 
in the blood of man, but commences as soon as the sexual forms 
reach the stomach of the mosquito, when after a certain time the 
evolution of the parasite reaches the sporozoite stage, these forms 
becoming lodged in the salivary gland of the mosquito where they 
remain until they again reach the human circulation during the 
biting process of the insect. 

Conditions, therefore, which favor the breeding of mosqui- 
toes increase the likelihood of malarial infections being pres- 
ent in a locality, and as heat and moisture are necessary require- 
ments for their propagation, it follows that the disease will be more 
prevalent in tropical and subtropical countries than in the more tem- 
perate zones. It is not, however, confined to the tropics. The march 
of civilization will in the natural order of events eliminate the disease 
in most temperate climates, while in the warmer ones the infection 
will remain endemic on account of the peculiar conditions favorable 
to mosquito life, which in many instances are hard to meet, or, at 
all events, the meeting of such conditions would involve the expen- 

26 



ETIOLOGY THE MALARIAL PARASITES. 27 

diture of immense sums of money, for which, up to the present 
time, the public have not been educated to the point of seeing the 
necessity. In the warmer climates the disease while endemic will be 
marked by exacerbations that depend on meteorological and certain 
other conditions. An example of what the natural trend of civili- 
zation will do toward the elimination of malaria, without any special 
attention being paid to the matter, is its disappearance from many 
portions of our Middle Western, and certain of our Eastern states, 
where at times in the past it was very prevalent, but is now 
practically extinct. In a great deal of this territory thirty or forty 
years ago the disease was common, but as soon as the land was 
cleared up, properly drained, and settled, malaria began to decrease 
and has slowly disappeared, without any special sanitary measures 
being adopted. 

The work, commenced by Laveran, carried on by Manson, Ross, 
and others, together with the recent observations of Darling, show- 
ing that the sexual forms of the parasite are amenable to the action 
of the quinin salts — it being previously maintained that this drug 
has no action on these forms — has made possible the inauguration 
of a campaign that would, if consistently carried on, wipe out this 
infection entirely. Osier, many years ago, writing on the impor- 
tance of the discoveries of Laveran and Ross, said, "One of the 
greatest scourges of the race is now at our command," and it is a 
matter of regret that with this command of the situation more has 
not been accomplished toward the eradication of a disease that 
results in so much suffering. 

It is safe to say that, if the mortality rate were higher than it 
is in most sections where malaria prevails, greater advancement 
would have been made in the past decade toward its complete 
eradication than has been the case. That "familiarity breeds con- 
tempt" never had a better illustration than is seen in the attitude 
of the people at large in malarial districts. Even among the 
educated and in those who believe in the mosquito transmis- 
sion of the disease, this indifference displayed toward possible, 
and in many instances probable, infection is very appalling and a 
matter of discouragement to the sanitarian in malarial sections. 
Little attempt is made to guard against infection, which results 
in the presence of malaria in many places, where, by a very little in- 
dividual prophylactic work, it could be stamped out very easily 
in a short time. 



28 MALARIA. 

In striking contrast to this condition stands out the very successful 
elimination of yellow fever from the United States, and foreign 
dependencies, and an illustration of the possibilities of a campaign 
against malaria is seen in the marked reduction of this disease to- 
gether with yellow fever in Havana. Gorgas states that, in 1900, 
the year before active work against the mosquito was commenced, 
there occurred in that city 325 deaths from malaria ; during 1901, 
the year that work was commenced, there were 151 deaths from this 
cause ; in 1902, 77 ; and in 1903, the mortality from malaria reached 
the low figure of 45. 

CLASSIFICATION OF THE MALARIAL PARASITES. 

There have been many classifications of the malarial plasmodia 
proposed by various writers on the subject, and a number of de- 
scriptions of the species, and while they are all of interest to the 
zoologist, a lengthy discussion of them would be of little practical 
interest to the general practitioner. The classification suggested 
by Craig is a complete one, and will be followed to the exclusion of 
others in the following pages. 

The classification is as follows : 

Division — Protozoa. 
Class — Sporozoa. 
Order — Hagmosporidia. 
Genus — Plasmodium. 
Species — 

1. Plasmodium malar ice (Marchiafava and Celli). Quartan ma- 
larial Plasmodium. 

2. Plasmodium vivax (Grassi and Feletti.) Tertian malarial 
Plasmodium. 

3. Plasmodium falciparum (Dlanchard). Estivo-autumnal 
Plasmodium, tertian type. 

Subspecies — 

4. Plasmodium falciparum, quotidianum (Craig, 1909). Quo- 
tidian estivo-autumnal Plasmodium. 

Before taking up in detail the morphology, biology, and staining 
qualities of these various species, a brief description will be made 
of the cycle of evolution that takes place in man's circulation, and 
that occurs in the body of the mosquito, common to all of the species. 



ETIOLOGY THE MALARIAL PARASITES. 29 

There are two distinct forms of evolution necessary for the .con- 
tinuation of the life of these organisms, each complete of itself, 
but nevertheless depending on the other. One takes place in the 
blood of man, is of an asexual nature, termed schizogony ; the other 
in the body of certain species of mosquitoes, is of a sexual nature, 
and termed sporogony. Ross, Marchiafava, Grassi, MaeCallum, 
Celli, and others have carefully studied the forms undergoing evolu- 
tion in both the human and mosquito cycles. The observations of 
these workers have been confirmed by all who have studied the 
morphology of the parasites. 

SCHIZOGONY. 

The zoological terms applied to the forms of the parasite observed 
in schizogony are the schizont, the merozoite, and the trophozoite. 
The schizont is a common term applied to all asexual forms result- 
ing from the sporozoite injected by the Anophelinas in her saliva, in 
the biting process, and those asexual forms resulting from the 
merozoite. The merozoite is that form which results from the sporu- 
lation of the fully grown schizont, and which re-enters the corpuscle 
to continue schizogony. The trophozoite is the young hyaline 
form that develops following the penetration of the corpuscles by 
the sporozoites and the merozoites. These forms are not seen in 
the mosquito and until their successful cultivation in vitro by Bass 
were not known to develop outside the human body. The schizonts 
are thin bodies resulting from the injection of sporozoites from the 
mosquito and from the merozoites, the product of sporulation. 
Sporozoites are needle-shaped forms that penetrate the red cor- 
puscle and immediately assume ring shapes, these being termed 
trophozoites. At first non-motile, they gather pigment from the 
hemoglobin assimilated, gradually assuming activity, which in- 
creases up to a certain age of the parasite, after which it 
decreases. Depending on the species, they then assume various 
shapes and develop certain differential points in their morphology, 
and as development proceeds the corpuscles, occupied, undergo cer- 
tain changes, also depending on the variety. Reaching the sporu- 
lating stage the corpuscle is destroyed ; the full-grown plasmodia 
are divided into a number of spores; these spores known as mero- 
zoites, re-enter the red corpuscles, and the evolution is once 
more under way. This cycle is completed in twenty-four, 
forty-eight, or seventy-two hours, depending on the species, 



30 MALARIA. 

hence the terms quotidian, tertian, and quartan malaria 
The author has found that a certain amount of confusion has 
arisen among students from the terms tertian and quartan malaria. 
In the former, while the cycle of the parasite is completed within 
forty-eight hours, the resulting chill takes place every third day, 
and on this account the name tertian has been applied, but it should 
be clear in the minds of all that the cycle does not take -three days 
for its completion. Thus a chill taking place on Monday is followed 
by another on Wednesday, or the third day, the cycle of the 
Plasmodium vivax (tertian malaria) being completed in forty-eight 
hours. So, also, in the quartan type, the cycle of the Plasmodium 
malarice is completed in seventy-two hours, but results in a chill, or 
exacerbation, every fourth day. 

FORMATION OF GAMETES. 

While the cycle known as sporogony takes place in the mosquito, 
the sexual bodies, or gametes, as they are called, originate in the 
blood of man. They are known as macrogametes (female), and 
microgametocytes (male), but while formed in the blood of man, 
are incapable of further development in the human circulation. 
Although the development of a microgametocyte to that of a fully 
formed microgamete is part of the cycle that takes place in the mos- 
quito, and will be described in discussing the forms of evolution 
that take place in the body of this insect, this phenomenon may 
under certain conditions be observed in human blood, but only after 
it has been withdrawn from the circulation. 

It has been a debated question whether gametes result from a 
separate class of sporozoites specifically intended for gamete for- 
mation, or whether the sporulating forms resulting from schizogony, 
by the action of the human host, cause certain of the merozoites to 
assume gamete formation. The latter theory is the one that is now 
generally accepted. Craig writes, "I believe with Schaudinn that 
the gametes are produced only after the plasmodia have undergone 
sporulation for some time, and that, therefore, they are of human 
origin, being differentiated during the process of schizogony, and 
not introduced as such by the infected mosquito. In other words, 
all of the sporozoites introduced by the insect develop into schizonts, 
the gametes or sporonts developing from a schizont after a certain 
period of time, some of the merozoites being thus differentiated. ' ' 



EXPLANATION TO PLATE 

SCHIZOGONY — The mosquito (A) in biting man injects sporozoites (1) which immedi- 
ately upon entering the circulation assume ring forms (2) ; as evolution advances 
the young schizont (3) is formed which gradually enlarges as evolution pro- 
ceeds (4). Toward the end of the human cycle the sporulating form (5) is seen, 
which in turn produces a number of merozoites (6). Each of these young merozo- 

ites (7) now re-enter other red cells (follow > >■ ) and, repeating the process 

begun by the original ring form (2), continue schizogony indefinitely; thus multi- 
plying the number of parasites by many times every sporulating period. 

SPOROGONY — However, after schizogony has continued for a certain number of days, 
certain of the merozoites undergo a transformation evolving to sexual forms knowto 
as the macrogamete or female (8) and the microgametocyte or male (9). Neither 
of these forms can proceed further in the process of evolution so long as they re- 
main in the circulation of man, but as soon as they are ingested by the mos- 
quito (B) evolution is again under way (follow >— r — >• )• The first change 
that occurs is that of flagellation of the microgametocyte which results in the 
formation of the flagellate body (10), which in turn produces the fully developed 
microgamete (11). This form now penetrates and fertilizes the female form (12) 
resulting in a body which lodges itself in the muscular walls of the mosquito's 
intestine and known as an ookinete (13) which later evolves to the oocyst (14) 
from which evolve the sporozoites (15), these becoming lodged in the salivary 
glands and being free in the saliva of the mosquito with which they are injected 
by the insect into man's circulation (as shown at 1) — the cycle being thus com- 
pleted. 

Note : There is no attempt in the foregoing to follow each and every stage of evolu- 
tion that takes place in the circulation of man or in the body of the mosquito, it 
being the aim to simply bring out the salient points that take place in the evolution of 
the parasite. 



CYCLE OF THE MALARIAL PARASITE 
IN MAN AND THE MOSQUITO 






V 



^ 



•1 ' 

/3 






\ 



/J- 




*£5l 



V* 



Schx z o ycny 



^oro^cny 




/^ 



/ 




A. Mosquito Injecting (l) Sporozoites. 

2. Young ring form. 

3. Young schizont. 

4. Older schizont. 

5. Sporulating Plasmodium. 

6. Young merozoites. 

7. Merozoite, continuing process of schizogony. 

8. Macrogamete (female sexual form). 

9. Microgametocyte (male sexual form). 

B. Mosquito becoming infected with the sexual forms while feeding on 
blood of infected man. 

10. Flagellate body. 

11. Microgamete. 

12. Microgamete fertilizing female. 

13. Ookinete. 

14. Oocyst. 

15. Sporozoites. 



ETIOLOGY THE MALARIAL PARASITES. 31 

SPOROGONY. 

After the mosquito has taken a meal of fresh blood from a man 
infected with malaria, containing the sexual forms of the parasites, 
both macrogametes and microgametocytes, the first form of evolu- 
tion takes place in the male, consisting of exflagellation. This is a 
process in which the microgametocyte throws out long thread-like 
filaments, numbering from one or two to eight, and measuring in 
length from two to four times the diameter of the parent body 
from which I hey are given off and detach themselves. These fila- 
ments become actively motile, and the remaining body undergoes 
degeneration. This process of exflagellation, normally occurring 
in the body of the mosquito within half an hour from the ingestion 
of the infected blood, can be observed, as mentioned previously, 
in the human blood after its being withdrawm from the circulation, 
by carrying out the following technic, given by Cabot : 

' ' Cut an opening one half by one inch in a piece of thick blotting 
paper and moisten the paper in hot water. Spread two glass slides 
rather thickly with fresh blood, lay the blotting paper on one side, 
cover the cut opening by the other, specimen side down, and slip 
a rubber band about both. After fifteen or twenty minutes the 
slides and paper may be separated, and the two specimens dried." 

The slides may then be examined without staining if desired, but 
the flagellated bodies stain readily and are then more easily detected 
by those not perfectly familiar with them. The staining method 
will be described in the pages devoted to the staining of the various 
forms of the plasmodia. It should be fully understood that this 
process of exflagellation does not take place in the circulation of 
man under any circumstances and normally only occurs in the 
stomach of the mosquito. 

Flagellation having occurred in the stomach of the mosquito, 
these actively motile thread-like bodies, or flagella, the fully de- 
veloped microgametes, rapidly dance around until they come in 
contact with the female gamete, which they penetrate and fertilize, 
resulting in an oval body known as a zygote. This oval form soon 
becomes elongated, and becomes situated in the muscular walls of 
the mosquito's stomach, being then known as an ookinete, a motile 
protoplasmic body, containing pigment, with a chromatic mass, the 
nucleus, seen in the center, this developing into what is known as 
an oocyst. This has a diameter of about 7 microns, which rapidly 



32 MALARIA. 

enlarges, finally reaching from four to eight times its original size, 
containing within it the fully developed sporoblasts. From the 
external layers of these, develop the sporozoites, thin elongated 
needle-shaped filaments, which find their way to, and become im- 
bedded in, the salivary glands of the insect. Later on, the ducts 
of this gland will be found to contain these bodies, being also free 
in the saliva, with which secretion they are injected into the blood 
of man by the insect, in the biting process. These glands are 
capable of harboring thousands of these filaments, the number in- 
jected at a single feeding being from a few to many hundreds. 

To recapitulate the evolution stages of the two cycles, gametes 
forming in the human circulation are withdrawn by the mosquito 
when biting, and by a series of stages of development in this insect, 
sporozoites are formed, which become lodged in the salivary glands, 
and are injected by the mosquito into the blood of man. These 
penetrate the red corpuscles, and by another series of changes of 
development in man, reach maturity and sporulate in certain fixed 
periods, depending on the variety; but this series of stages of de- 
velopment does not end the cycle in man, for the merozoite, the 
product of sporulation, now re-enters the red corpuscle, continuing 
the cycle by schizogony. After this has taken place for some days 
certain of the merozoites go on to the formation of gametes, which 
are then ready to be taken up by the mosquito, and the cycle of 
sporogony repeated in this insect. The question is often asked, 
'-if man gets the parasite from the mosquito, and the mosquito gets 
the parasite from man, where did the parasite originate, or which 
had the infection first?" As Ross says, this is like the question, 
if the egg comes from the hen, and the hen from the egg, which 
came first? All we know is that the parasite does alternately oc- 
cupy man and the mosquito, that in this way are the species per- 
petuated, that, so far as we know, man and the mosquito are the 
only necessary factors for their perpetuation, and that they are 
unable to reproduce except under this alternation of hosts. 

DESCRIPTION OF THE MALARIAL PLASMODIA. 

Tertian Malaria (Plasmodium Vivax, Figs. 1-5). — This organ- 
ism completes its human cycle (schizogony) in forty-eight hours, 
producing the typical "chills and fever," with an exacerbation of 
clinical symptoms occurring every third day. All stages of the 
development of this organism may be observed in the peripheral 



ETIOLOGY — THE MALARIAL PARASITES. 



33 



blood, although sporulation takes place principally in the circula- 
tion of the viscera and that of the deep tissues, and they are more 
easily recognized than any of the other species, and should for this 
reason be chosen for primary study by the novice working with 
malarial blood. It is a benign infection, and the common one of 
temperate climates, but is also prevalent in tropical and subtropical 
countries. 

The sporozoite having penetrated the red corpuscle, the young 
parasite is seen as a small hj^aline protoplasmic ring (Fig. 1), meas- 
uring 1.5 to 2 microns, of low refraction, and barely distinguishable. 
It is at first a non-motile body, but takes on ameboid movement 




1. — Plasmodium vivax (Tertian p] 
modium). Young ring forms. 



Fig. 2. — Plasmodium vivax (Tertian Plas- 
modium). Half grown parasite. 
(After Craig.) 



within a few hours, when fine pigment granules of a reddish-brown 
color form, being derived from the hemoglobin, and distributed 
throughout the protoplasm; and as the organism develops it takes 
on various irregular shapes, the activity of the pigment granules, 
which is very pronounced, being responsible for this. Minute 
pseudopodia may be observed rapidly pushing out and withdrawing 
themselves; with the growth of the parasite motility increases, and 
the organism is seen to frequently change its position in the cor- 
puscle ; the pigment granules increase, continue actively motile, 
and in the fresh specimen may be observed dancing around. At 
the end of twenty-four hours the Plasmodium occupies fully half 
of the red corpuscle (Fig. 2), which by this time has increased fully 
two-thirds over its original size; ameboid motion decreases, and 



34 



MALARIA. 



twelve hours later has practically ceased, the pigment remaining 
active. In a few more hours, or four or five before the completion 
of the forty-eight-hour cycle, the pigment collects at or near the 
center of the fully grown organism, while the protoplasm is seen to 
be dividing in a radial manner (Fig. 3), resulting in the formation 
of from twelve to twenty-four ovoid bodies or spores, merozoites, 
which are arranged in two irregular circular rows, one within the 
other. (Fig. 4.) By this time the corpuscle is hardly visible, only 
a very pale and faint outline of the cell being seen, and even this 
soon disappearing, the red corpuscle being destroyed and sporula- 




Fig. 3. ^Plasmodium vivax (Tertian Plas- 
modium). Presegmenting parasite. 
(After Craig.) 



Fig. 4. — Plasmodium vivax (Tertian Plas- 
modium). Segmenting tertian par- 
asite. (After Craig.) 



tion completed. The young merozoites now penetrate other red 
(Fig. 5) cells, to go through the same process, continuing the cycle 
of schizogony for more or less indefinite periods, depending on the 
resistance offered by the infected individual, and the treatment 
instituted, or both. It has always been thought that with sporula- 
tion completed the merozoiter became free in the blood-plasma, but 
the research work of Bass and Johns, recently conducted in 
Panama, in connection with the cultivation of the plasmodia in 
vitro, demonstrated the interesting fact that the merozoites die 
almost immediately in blood plasma. Bass is of the opinion that 
the merozoites only enter the other red cells by direct contact of 
the cells at the time of segmentation. In a personal communica- 
tion to the writer he describes the process as follows : "A para- 
site grows larger and larger until it finally is too large to pass 



ETIOLOGY — THE MALARIAL PARASITES. 



35 



through the smallest capillary. The consistency of the substance 
of the parasite is quite different from that of the red cells and is 
very much less yielding. It, therefore, cannot change its shape 
very much to accommodate the capillary. It continues to grow 
and other red cells naturally float up against it. Finally, whenever 
segmentation takes place, if the opening in the infected cell occurs 
opposite another cell now packed against it, the young merozoites 
pass directly into the new red cell before they are exposed to the 
plasma, which is extremely destructive to parasites." 

The changes observed in the red corpuscles invaded by the tertian 




Fig. 5. — Plasmodium vivax (Tertian Plasmodium). 

(After Craig.) 



Total separation of the spores. 



parasite are very marked, and are sufficient in themselves to differ- 
entiate this type of infection from other forms. Soon after, the 
sporozoites from the mosquito, or the merozoites formed by sporu- 
lation, invade the cells, these cells immediately become distended 
and gradually increase in size until, by the time the parasite has 
assumed its full growth, they are often two or three times their 
ordinary size, and only a faint outline of the rim is visible. They 
also lose their regular contour, having been formed into all sorts 
of shapes by the contained parasites which assume fantastic forms 
on account of the activity of the pigment. The hemoglobin that 
forms the pigment is assimilated by the parasite, and this results 
in the decolorization of the corpuscle, which is seen early, as is also 
the increased size of the cell, so that any cells either enlarged or 
pale in color should be carefully scrutinized for the detection of 



36 MALARIA. 

parasites. It is not uncommon to see a cell with a double infection : 
that is, one containing two young forms. This phenomenon, which 
is of considerable significance under certain conditions in the eti- 
ology of recurrences, will be discussed at another time. 

Another important change is the formation of granules, known 
as Schuffner 's dots, in the infected cells, producing a stippled effect, 
and the presence of these, plainly brought out in the stained speci- 
men, is significant of tertian infections. Craig states that he has 
seen them in quartan infections, but only rarely, and considers their 
occurrence in these infections as of such rarity as to be of no prac- 
tical importance, and that in the few quartan cases in which he 
has observed them it was in the older forms and in no instance with 
the young rings, which leads him to consider that all cases showing 
ring forms accompanied by Schuffner 's dots are undoubtedly tertian 
infections. 

Other changes occurring in the blood, such as reduction of red 
corpuscles, loss of hemoglobin, and alterations in the relative count 
of the leucocytes, will be discussed in considering the pathology of 
malarial infections. 

Quartan Malaria (Plasmodium Malariae, Figs. 6-8). — The cycle 
of this species of malarial plasmodia is completed in 72 hours, an 
exacerbation of the clinical symptoms occurring every fourth day, 
and concomitant, as in all types of malaria, with the sporulation of 
the parasites. It is not so common as either the benign tertian or 
the estivo-autumnal infections. The author has seen but two cases 
in the state of Florida, and while on duty with our troops in the 
Philippine Islands in 1900-1901, saw but three or four cases in a 
total of many hundreds of cases of malaria. Schizogony may be 
observed in all stages of evolution in the peripheral circulation of 
man, the sporulating forms of this species being encountered more 
frequently in the peripheral circulation than in any of the other 
species. 

The careful observer will have no difficulty in differentiating this 
organism from the Plasmodium vivax. As first seen in the red cor- 
puscles it appears as a small hyaline non-motile ring, being more 
refractive than the tertian parasite, slightly larger, and does not 
produce enlargement of the invaded cell, so characteristic of the 
organism just described. In the early pigmented forms about one 
quarter of the corpuscle is occupied, and as the pigment develops 
the parasite assumes motility, which is, however, much less pro- 



ETIOLOGY — THE MALARIAL PARASITES. 



37 



nounced than in the tertian form. The pigment is much coarser 
than in the tertian parasite, of a dark-brown color, and much less ac- 
tive — it will be remembered that the pigment of the tertian organism 
is extremely active, being made up of fine granules and of a reddish- 
brown color. (Fig. 6.) At the end of twenty-four hours motility 
is practically absent, the protoplasm appears granular, is more 
distinct in outline, and the pigment tends to collect on the edges 
of the Plasmodium, sometimes forming a circular band on the 
periphery of the organism, which may at this time take on tri- 
angular or oval forms. 

At the end of thirty-six hours pigment has considerably increased, 
is non-motile, and the corpuscle, instead of being considerably en- 




Fig. 



-Plasmodium Malariae (Quartan Plasmodium), 
(After Craig.) 



One-quarter-grown parasite. 



larged as in the tertian form, tends to retract around the parasite, 
which is very refractive, occupies but half or less of the cell; and 
there is no decided change in the organism for several hours follow- 
ing. From six to ten hours before sporulation, the pigment, which 
has collected on the periphery of the parasite, is seen to scatter 
throughout the protoplasm and is non-motile, and the parasite, 
spherical in shape, remains devoid of ameboid movement ; but as the 
sporulation stage is neared the pigment is seen to collect in the 
center of the organism, while the protoplasm divides, in a similar 
radial manner to that seen in the tertian, forming separate and 
distinct bodies, the merozoites. (Figs. 7 and 8.) Another marked 
point of differentiation between the tertian and quartan parasites 



38 



MALARIA. 



is that, while, in the former, speculation results in the formation of 
from twelve to twenty-four spores, or merozoites, arranged in two 
irregular circular rows, the quartan sporulating stage results in 
from six to twelve segments, arranged in a single circular row 
around the pigment body. The presporulating body generally fills 
the invaded cell entirely, which becomes invisible, but in some in- 
stances segmentation occurs before the whole cell becomes occupied. 
Sporulation completed, the merozoites enter other red cells, as in 
tertian malaria, repeating the schizogonic cycle, but it should 
be remembered that in all infections, after schizogony has 
gone on for a certain, at present undetermined, period, certain of 
the merozoites undergo a transformation to gametes, resulting in 




Fig. 7. — Plasmodium Malaria? (Quartan 
Plasmodium). Presegmenting par- 
asite. (After Craig.) 



Fig. 8. — Plasmodium Malaria? (Quartan 
Plasmodium). Segmenting parasite. 
(After Craig.) 



the fully formed sexual organisms, which are taken up by the mos- 
quito and undergo evolution in the body of this insect. 

The changes taking place in the blood in quartan infections are 
as follows: The corpuscle, instead of enlarging and taking on 
irregular shapes, as in the tertian, becomes retracted around the 
parasite, is smaller, or else remains unchanged in size, and does 
not assume the pale color common to cells infected with the tertian 
parasite, but takes on a dark-green color. There is also an absence 
of Schuffner's dots, described in tertian infections. Craig's state- 
ment that these may occur in quartan infections has been discussed, 
and it will be remembered that, while in exceptional cases these 
dots may be seen after the organism has taken on growth and lost 
the ring form, they are never seen in conjunction with this form. 



ETIOLOGY THE MALARIAL PARASITES. 



39 



Tertian Estivo- Autumnal Malaria (Plasmodium Falciparum, 
Figs. 9-11). — This is the most common of the estivo-autumnal 
infections, and has been more often reported than the quotidian 
type. The cycle is completed in forty-eight hours, or sometimes a 
little less, and attended with exacerbations of symptoms every third 
day. Double invasion of a cell and even multiple infections are 
a common occurrence in this type of the disease. (Fig. 9.) The 
parasite as first seen is a hyaline ring (Fig. 10), usually round but 
occasionally taking on oval shapes, and while it is somewhat hard 
to differentiate from the very early forms of the quartan parasite, 
a close and careful observation will bring out certain differential 




Fig. 9. — Plasmodium falciparum (Te'r- 
tian estivo-autumnal Plasmodium). 
Multiple invasion with the estivo- 
autumnal parasite. 



Fig. 10. — Plasmodium falciparum (Ter- 
tian estivo-autumnal Plasmodium). 
Young ring forms. (After Craig.) 



points in its morphology. It is considerably smaller than either 
of the parasites previously described, and as the schizont de- 
velops the difference in morphology allows of no mistake. 
The infected cell appears smaller and is of a green color. In 
the young forms of the parasite the protoplasmic ring is broader 
at one point of its periphery than the remainder, giving to it a 
characteristic "signet-ring" appearance; it is a very refractive or- 
ganism and possesses but slight ameboid motion. Pigment is 
formed while the parasite is in the ring form, usually appearing, 
in the broad part of the protoplasmic ring, at about the end of 
eighteen hours; the granules are of a reddish color and are motile 
but not so actively as in the benign tertian parasite. The organ- 



40 



MALARIA. 



ism loses its ring form at about the end of twenty hours, at which 
time about half of the cell is occupied'; ameboid motion always 
sluggish becomes then even more so. As the presegmenting stage 
is reached the parasite occupies about one third of the cell, the 
pigment collects in a single mass in or close to the center of the 
organism, the usual radial segmentation takes place, as in the forms 
already described, resulting in the formation of from ten to eight- 
een merozoites, which are arranged very irregularly and not in the 
definite circular arrangement described in the tertian and quartan 
types. (Fig. 11.) The merozoites continue the schizognic cycle 
in the same manner in all types of malaria. Sporulation of this 




Fi< 



11. — Plasmodium falciparum (Tertian estivo-autumnal Plasmodium). Segmenting 
form of the parasite. (After Craig.) 



parasite in the peripheral blood is rarer than in the benign tertian, 
being seldom seen there, taking place almost entirely in the visceral 
circulation. 

The changes occurring in the red corpuscles will be discussed 
with those taking place in the quotidian estivo-autumnal type, with 
which they are common. 

Quotidian Estivo-Autumnal Malaria (Plasmodium Falciparum 
Quotidianum) . — This species of the malarial parasite completes its 
cycle in twenty-four hours. While it is claimed that it is rather 
confined in its area of distribution, the author has encountered it in 
Florida, and is rather of the opinion that it is of greater frequency 
in the Southern states than is generally believed. 

Like other varieties of the plasmodia, it is first seen in the red 



ETIOLOGY THE MALARIAL PARASITES. 41 

corpuscle as a small, round, hyaline ring and early assumes great 
activity, rapidly increasing in size, the young schizont occupying 
about a sixth of the infected cell. At first an indistinct body, it 
soon becomes very refractive, and the outline of the organism is 
well defined. The infected cell early becomes smaller than the 
surrounding ones, is often crenated, and appears to be shrunken. 
The signet-ring appearance, just described as characteristic of the 
malignant tertian, is not seen in this variety, the young plasmodia 
are considerably smaller, and ameboid motion is much more marked. 
It will be remembered that the pigment develops in the malignant 
tertian while the parasite is still in the ring form; in this type of 
infection pigment is not observed until the ring form is lost. The 
granules are very scanty, there seldom being but two or three and 
more often but a single one ; they are entirely devoid of motion, thus 
differentiating this parasite from all other pigment forms, are of 
a dark brown or sometimes black color, generally situated near the 
center, but occasionally on the side of the organism. The infected 
cells have been termed "brassy corpuscles," owing to the peculiar 
color they assume in this infection. 

Sporulation seldom takes place in the peripheral blood, but niay 
be observed in blood specimens taken by splenic puncture, or, in 
post-mortems, in blood from the deep tissues. It takes place at the 
end of twenty-four hours and, following radial striation, the pre- 
sporulating plasmodia is composed of six to eight round bodies, the 
merozoites. The quotidian are smaller than the malignant tertian 
merozoites, and the entire presporulating body occupies, as a rule, 
not more than a quarter of the infected cell. 

The red corpuscles when invaded by either of the estivo-au- 
tumnal parasites become very much smaller. It will be remembered 
that in the benign tertian infections the cell is very much enlarged, 
of irregular shape, characterized by the presence of Schuffner's 
dots, and becomes pale; that in the quartan infections it becomes 
smaller, assumes a green appearance, and may be retracted. The 
decrease in the size of the cell invaded by the estivo-autumnal para- 
site is very much more marked, and the infected corpuscle becomes 
a darker green. In the quotidian variety the cells are more wrin- 
kled or shrunken and more crenated than in the malignant tertian, 
while the brassy corpuscles seen in both types of estivo-autumnal 
infections are especially common in the quotidian. Schuffner's 
dots are not present in either of these infections. 



42 MALARIA. 

While the changes occurring in the red corpuscles in the benign 
tertian are so characteristic as to allow of no error, and would be 
sufficient in themselves to make a diagnosis, the changes observed 
in the quartan and the estivo-autumnal infections are much less 
marked, and unless one is perfectly familiar with the blood pic- 
ture of these malarial infections, errors are easily made. In both 
the quartan and the estivo-autumnal infections there is a decrease 
in the size of the corpuscle, the extent of which depends on the in- 
fecting organism. 

The tabulation of differential characteristics of the various para- 
sites, together with the changes taking place in the corpuscles, shown 
in Table I, will be of assistance in arriving at the determination of 
a species. 

STAINING REACTIONS OF THE PLASMODIA. 

The staining reactions of the various species of malarial 
Plasmodia, as seen in the peripheral blood of man, are common to 
all species. While any of the stains described later may be 
used, the author has used with universal success Wright's modi- 
fication of the Leishman stain. The technic of the application 
of this staining fluid, together with that of other staining 
methods, will be found in another chapter. With familiarity, 
which is easily acquired, in the use of this stain, the resulting pic- 
ture renders a laboratory diagnosis of the malarial infections an 
easy matter. 

Tertian Parasite. — For reasons already given, the tertian para- 
site is the one of choice for the beginner to familiarize himself with. 
All of the forms of schizogony may be seen in the peripheral blood, 
although sporulation occurs more generally in the deeper tissues. 
When stained the young parasite, a ring form, is seen to consist 
of a mass of protoplasm, staining an intense blue, containing a 
vesicular nucleus which holds within it a goodly amount of chro- 
matin, staining an intense red, and being the only portion of the 
nucleus that takes a stain. The blue-stained protoplasm surrounds 
this unstained area, and is thinnest at that portion of its periphery 
where the chromatin appears, in fact, may be almost invisible at 
this portion of the periphery, careful focusing being necessary to 
detect it. The unstained area representing the vesicular nucleus is 
spherical or oval and is in contact with a larger area, unstained or 
lightly stained about the same as a red corpuscle, which is of a 



ETIOLOGY THE MALARIAL PARASITES. 



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44 MALARIA. 

light pink or straw color. This larger area represents a vacuole 
that has formed alongside the nucleus. 

As the parasite loses its ring form, the activity of the pigment, 
as it forms in the young schizont, causes the organism to take on 
various fantastic shapes, which are very prettily shown in the 
stained specimen, many varieties of these shapes being seen in a 
single specimen. As pigmented forms develop, the pigment is dis- 
tributed throughout the protoplasm of the organism, the vesicular 
portion of the nucleus being gradually lost sight of. "With the 
further growth of the parasite the chromatin separates into small 
granules, becoming irregularly situated throughout the protoplasm, 
and does not take as intense a stain as formerly. As the presporu- 
lation stage is reached, the protoplasm, studded with pigment gran- 
ules stained a greenish-brown, increases in amount and takes a 
heavy stain; the chromatin is seen to be gathered in clumps and 
also stains intensely. When segmentation has taken place, and 
the merozoites are formed, the chromatin granules are seen in still 
larger clumps, staining a dark red, each surrounded by an un- 
stained area, these, being surrounded by small bands of protoplasm, 
staining blue; the pigment, as a rule, collects in a single mass in 
some portion of the protoplasm. The merozoites, having gained 
access to red cells, appear under the Wright stain as a small mass 
of protoplasm staining blue, enclosing an unstained oval area which 
has within it a small dot of chromatin staining a bright red. 

The staining reactions of this parasite may be summed up as 
follows: With the young ring forms is seen a small mass of 
protoplasm, thinner at a certain portion of its periphery, staining 
a deep blue; at that portion of the blue-stained protoplasm pre- 
senting the narrowest surface is seen a small particle of chromatin, 
which takes on a deep-red or sometimes a violet color, and sur- 
rounding this small mass is an unstained area, or one lightly 
stained as the corpuscle, this being a vacuole that has developed 
around the nucleus. As the parasite grows, the protoplasm in- 
creases in size, takes on irregular shapes, and contains more or less 
pigment scattered through it, which stains a greenish-brown. As 
sporulation advances, the picture is one that would be looked for 
with a knowledge of the changes taking place in the unstained 
specimen; the chromatin is seen to become divided, finally forming 
into small clumps, each of which later are seen as minute dots in 
the individual merozoites. The merozoite after sporulation takes 



ETIOLOGY THE MALARIAL PARASITES. 



45 



on the same staining reactions observed in the original young 
forms. 

Quartan Parasite. — The staining reactions of the quartan para- 
site are very much the same as observed in the tertian variety just 
described, but there are certain differences that may be seen by 
close observation. The protoplasm by comparison takes a more 
intense stain from the methylene blue, and the chromatin, gen- 
erally located in the center of the young schizont, takes a dark-red 
stain, while the young forms, which like the tertian are also ring- 
shaped, are slightly larger than those of the tertian variety. Char- 
acteristic of this form of malarial infection -are the "band forms" 
of protoplasm, staining a dark blue and occupying the diameter 




Fig. 12. — Plasmodium Malaru 



(Quartan Plasmodium). Band form of the parasite. 
(After Craig.) 



of the red cell, or nearly so. (Fig. 12.) They inclose a chromatin 
mass which stains in the usual red manner. 

The fantastic irregular shapes assumed by the tertian parasite 
are not seen in quartan infections, this parasite assuming a cir- 
cular contour. The pigment, not abundant, is not distributed 
throughout the protoplasm as in the tertian but tends to collect 
on the periphery of the organism. 

Estivo-Autumnal Parasites. — The staining reactions of the estivo- 
autumnal parasites present no especially significant characteristics. 
The ring forms present a very thin band of protoplasm, and the 
chromatin, instead of being contained within the periphery of the 
protoplasm, as it is in the tertian and quartan infections, often 
projects outside of the periphery. In the malignant tertian organ- 



46 MALARIA. 

ism pigment will be observed in the young ring forms contained 
in that portion of the protoplasm where it is the broadest. The 
small size of the ring form, the protoplasm being a thin band, sit- 
uated in a corpuscle smaller than those not infected, and often 
presenting a wrinkled or crenated appearance, will be sufficient 
to differentiate these organisms from either the benign tertian or 
the quartan. 

DESCRIPTION OF GAMETES AND STAINING QUALITIES. 

The sexual forms of the malarial plasmodia, destined for evolu- 
tion in the mosquito, have already been referred to as macrogametes 
(female), and microgametocytes (male), and the author has al- 
ready described the circumstances under which the latter become 
flagellate bodies, later giving off flagella, the fully formed micro- 
gametes. 

The gametes of the benign tertian are difficult to recognize in the 
fresh blood until they reach maturity. Unlike the schizont they 
retain a circular shape, being from two-thirds to twice the size of 
a red corpuscle, the macrogamete being slightly larger than the 
microgametocyte. 

The unstained macrogamete appears as a circular protoplasmic 
body containing much pigment, which is situated near the periphery 
of the organism in a wreath-like manner. It is non-motile, this 
being an important point in differentiating the female from the 
male, in which the pigment is actively motile. 

When stained by "Wright's method the protoplasm takes an in- 
tense blue; the chromatin, less in amount than in the fully de- 
veloped schizont, and situated near the periphery of the organism, 
stains, as in the schizont, a bright red. The pigment, already de- 
scribed as circling close to the periphery, is rod-like, massed ir- 
regularly, and very dark. 

The microgametocyte of tertian malaria is a smaller body than 
the female, being about the size of a red corpuscle or slightly larger. 
When maturity is reached it is free in the blood-plasma and is 
made up of protoplasm containing a large amount of pigment, and 
at first only slightly motile. Unlike the pigment arrangement in 
the macrogamete, which appears in a wreath-like manner near the 
periphery, in this organism it is irregularly distributed within the 
protoplasm. Under the conditions previously described, the pig- 
ment will be observed to increase in activity, collecting toward the 



ETIOLOGY THE MALARIAL PARASITES. 47 

center, this being* followed by decreased motility; and as this ac- 
tivity decreases, long thin filaments, numbering from two to six, 
the young microgametes, destined to fertilize the macrogametes, 
are seen to protrude from the periphery of the organism. They 
are extremely active and may be seen to lash about, finally be- 
coming free from the parent body, coming in contact with the 
female, which they penetrate and fertilize. This process normally 
occurs within the body of the mosquito, and sporogony is thus 
established. 

The staining reactions of the microgametocyte are similar to 
those seen in the female form. As already stated, the pig- 
ment is more abundant than in the macrogamete, being un- 
evenly distributed through the protoplasm, and staining a light 
green, the protoplasm a light blue ; while the chromatin, 
greater in amount, stains an intense red, which in the fully de- 
veloped organism is divided into several masses which occupy a 
position near the periphery of the body, and as the flagella develop, 
these divided chromatin masses become situated in the filaments, 
which later develop into fully formed microgametes. In these 
forms the protoplasm stains the usual blue, the chromatin taking 
on an intense red, increasing in amount after leaving the parent 
body, which undergoes degeneration. 

In the younger forms the gametes of the benign tertian may be 
differentiated from the young schizont, when stained, by the posi- 
tion of the red-stained chromatin, which occupies the center of the 
ring of blue-stained protoplasm. The nutrient vacuole, described 
in the young schizont, is absent in the gamete-trophozoite. 

The differences between the gametes of quartan malaria and 
those of the benign tertian are so minute that a separate descrip- 
tion of them is not necessary. In the young intracorpuscular 
forms, the smaller bodies together with absence of the increased 
size of the corpuscle will serve to differentiate them from the young 
tertian gamete. The nutritive vacuole is absent, but loses its 
significance as it is also absent in the young quartan schizont early 
in its development. 

The staining reactions of the fully developed forms are similar 
to those of the tertian variety. The macrogametes are larger 
than in the benign tertian, and contain less chromatin which re- 
mains as an intact mass. The microgametocytes are considerably 
smaller than the tertian, and the pigment contained in them is 



48 



MALARIA. 



much coarser. The fully developed microgamete has nothing to 
differentiate it from that of the tertian male gamete. 

What has been said in regard to the schizonts of the benign ter- 
tian infection, as being suitable for the novice to work with, is 
equally true of the sexual forms of the estivo-autumnal infections. 
The peculiar crescentic formations assumed by these bodies make 
their identification an easy matter, and once they are seen and 
recognized, it is impossible to mistake them or to fail to properly 
recognize them. When once formed in the blood they are the most 
persistent and the hardest forms to eradicate, but they are not 
present in all cases; in fact, the majority of cases fail to reveal 
the presence of sexual forms. Craig is of the opinion that a care- 




Fig. 13. — Plasmodium falciparum (Tertian estivo-autumnal Plasmodium). Female 
crescent. Macrogamete. (After Craig.) 



ful examination of the peripheral blood will show crescents in 50 
per cent of the infections, but has been unable to demonstrate 
them in but a little over 33 per cent of his examinations; but he 
thinks that a careful examination of smears from the spleen or 
bone marrow will greatly increase their percentage. It is espe- 
cially in these infections, requiring a long and persistent examina- 
tion of the peripheral blood for the detection of the sexual forms, 
this detection being such an important factor in the prophylaxis 
of the disease, that the application of the thick-film method in the 
examination of blood, originally advocated by Ross, is of especial 
value; this method will be dwelt on at length in another chapter. 
The morphology of the sexual forms in both types of estivo-au- 



ETIOLOGY THE MALARIAL PARASITES. 



49 



tumnal infection are very similar, the only differences being in the 
general contour and size, and will be considered together. Both 
forms, male and female, assume ereseentic shapes and develop within 
I lie red corpuscle. 

The maerogamete (Fig. 13) is characterized by its long slim 
ereseentic form ; it measures in length from one and a half to two 
times the diameter of a normal red corpuscle. Pigment collects 
in the center of the organism, is non-motile, and is usually seen in 
an irregular mass in this position, but may assume a wreath-like 
arrangement slightly removed from the center. After becoming 
extracorpuscular, the maerogamete is of an ovoid shape, later tak- 




U — Plasmodium falciparum (Tertian estivo-autumnal Plasmodium). Mule crescent. 
Microgametoeyte.- - I Ann- ( ra ig. I 



ing on the form of a crescent. There are but slight differences in 
the maerogamete of an estivo-autumnal quotidian and an estivo- 
autumnal tertian. The former is slightly smaller, and the pig- 
ment contained within the female gamete is in the form of fine 
granules, while in the tertian il is rod-like, and in a larger 
amount. 

The protoplasm of the maerogamete stains a light blue still lighter 
in the center, which contains the chromatin, stained red. The pig- 
ment, as previously described as assuming a wreath-like appearance, 
surrounds the chromatin, and is stained a dark-green color. The 
corpuscle containing tlu- organism is generally barely discernible, 
close inspection showing it in the t'orin of a ribbon-like band closely 



50 MALARIA. 

adherent to the external surface of the organism and stained a 
yellowish-pink or straw color. 

The microgametocyte (Fig. 14) of the est ivo -autumnal infec- 
tions is differentiated from the female by the bean-like shape of the 
organism. It will be recalled that the macrogamete is a long slen- 
der crescentic form ; the male or microgametocyte is shorter, thicker, 
and of a bean-like shape. The pigment is finer, and instead of 
being collected in the center in a mass or wreathed near the center 
as in the macrogamete, is distributed throughout the protoplasm 
of the body, or may be collected at the extremities. When trans- 
ferred to the body of the mosquito it throws out flagella, common 
to all microgametocytes, which penetrate the females and fertilizes 
them. 

The staining of the microgametocyte is similar to that of the fe- 
male form, except that the stains are taken more deeply, the proto- 
plasm staining a deeper blue, while the chromatin, distributed 
throughout it, takes a light red or pink, and the pigment, situated 
at either end of the crescent, an indistinct greenish-brown. The 
appearance of the remaining corpuscle is similar to that containing 
a macrogamete. 

The microgametes are the flagella thrown out by the micro- 
gametocyte on reaching the body of the mosquito. As they are 
being formed, the microgametocyte loses its crescentic or bean-like 
shape, and assumes a more circular form, the pigment becomes ac- 
tively motile, and filaments are thrown out, these numbering from 
one to three in number, occasionally four, and when disengaged 
from the parent body, constitute the fully developed microgametes. 
The general description of the microgamete of the benign tertian 
applies to the microgamete of all species, it being impossible to 
differentiate between those of any of the malarial infections, and 
their staining qualities are also exactly similar. 

The young gametes when stained by Wright's stain may be dif- 
ferentiated from the young schizonts by the following character- 
istics : the chromatin in the gamete is observed in the center of 
the organism instead of on the periphery, as seen in the schizont; 
pigment is in larger amount, is not so motile as in the schizont; 
and the protoplasm stains a more intense blue. 



CHAPTER III. 

ETIOLOGY— THE MALABTA-CAK HYING 
MOSQUITOES. 

In discussing the etiology of malaria with the laity, the general 
practitioner will often find the erroneous opinion held that any 
and all mosquitoes may transmit the disease. While a great num- 
ber of species have been mentioned as possible carriers by various 
writers, the list of which I will not burden the reader with, the 
following are those that have been actually incriminated as ma- 
laria carriers, this list being one compiled by Craig: 

GENTS, Anopheles. A. maculipennis, Meig; A. bifurcatus, Linn; A. al- 
geriensis, Theo. ; A. jasoensis, Tsuzuki; A. formosaensis, Donne: A. cohaesus, 
Donne; A. quadrimaculatus, Say; A. albipes, Giles; A. vagus; A. vincenti; A. 
martini; A. pursati. 12 species. 

GENUS, M yzomyia. M. listoni, Liston; M. funesta, Giles; M. turkhudii, 
Liston; M. cidicifacies, Giles; M. nili. Theo.; M. hispaniola, Theo.; M. lud- 
Imrii. Theo.; .1/. lutzii, Theo. 8 species. 

GENUS, Stethomyia. 8. nimba, Theo. 1 species. 

GENUS, Pyretophorus. P. costalis, Loew: chaudoyei, Theo. : P. ardensis, 
Theo.: P. superpictus, Grassi; P. jeyporensis, Theo. 5 species. 

GENUS, Arribalzagia. A. maculipes, Theo. 1 species. 

GENUS, Myzorhynchus. M. sinensis, Wied; .1/. barbirostris, Van der Wulp; 
.1/. pseudopictus, Grassi; M. paludis, Theo.; M. mauritianus, Grandpre and 
Charmoy; .1/. coustanii, Lav. (i species. 

GENUS, Nyssorhynchus. N. fuliginosus, Giles: N. stephensii, Liston; .V. 
maculipalpis, Giles; N. theobaldii, Giles. 4 species. 

GENUS, Cellia. C. argyrotarsis, Robineau-Desvoidy ; ('. pharoensis, Theo.; 
C. albimanus, Wied. 3 species. 

He gives the geographical distribution of these species as follows : 

West Indies: Cellia argyrotarsis, Cellia albimanus. 

Canada: Anopheles maculipennis. 

United States: Anopheles maculipennis, Anopheles quadrimaculatus, ('cilia 
argyrotarsis. 

Central and South America: Anopheles albipes, Arribalzagia maculipes, 
Pyretophorus lutzii, Cellia argyrotarsis, Myzomyia lutzii, Cellia albimanus. 

Europe: Anopheles maculipennis, Anopheles bifurcatus, Myzorhynchus 
pseudopictus, Pyretophorus superpictus, Myzomyia hispaniola. 

Asia: India — Myzomyia cuUcifactes, Myzomyia listonii, Myzomyia turk- 
hudii, Pyretophorus jeyporensis, Myzorhynchiis barbirostris, Myzorhynchus 

51 



52 MALARIA. 

sinensis, Nyssorhynchus theobaldi, Nyssorhynchus stephensii, Nyssorhynchus 
fuliginosus, Nyssorhynchus maculipalpis. 

Japan: Anopheles jesoensis, Anopheles formosamsis, Anopheles cohwsus. 

Africa: Myzomyia funesta, Myzomyia nili, Pyretophorus costalis, Pyre- 
tophorus ar den sis, Pyretophorus chandoyei, Myzorhynchus barbirostris, My- 
zorhynchus mauritianus, Myzorhynchus paludis, Cellia pharoensis. 

Madagascar : Myzorhynchus coustanii. 

Mauritius : Myzorhynchus mauritianus. 

The Philippine Islands : The following malarial mosquitoes have been found 
in the Philippine Islands by Ludlow, Whitmore, Banks, and the writer: 
Myzomyia funesta, Myzomyia ludlowii, Myzorhynchus barbirostris, Myzorhyn- 
chus sinensis, Nyssorhynchus fuliginosus. Further observation .will undoubt- 
edly demonstrate that other species occur in these islands. 1 



HABITS OF THE ANOPHELINES. 

A general knowledge of the habits of the Anophelines is essential. 
It may be generally stated that they are night feeders, and that 
those persons who keep themselves protected from sundown to sun- 
rise will escape infection. This was markedly demonstrated by 
Doctor Sambon and his associates in the Roman Campagna, and 
yet it is probable that under certain conditions, and in certain 
climates, there are exceptions, to this rule. Craig states that, in the 
Philippine Islands, he has frequently observed the Myzomyia funesta 
feeding in the early morning and even at noon, and Le Prince, 
Chief Sanitary Inspector of the Isthmian Commission, in a study 
of mosquitoes seen in Panama, writes as follows: 

The albimanus generally leaves the dwelling during the daytime. It is 
present and bites more readily after dark. However, it will bite voluntarily 
at any hour of the daytime, but does so mostly indoors or out of the direct 
rays of the sun. If Anophelines are resting in vegetation near houses, and such 
vegetation is disturbed, burned, or removed, they will often seek shelter in the 
nearest buildings. This habit is common to other mosquitoes in the tropics. 
In a badly infested vicinity such a removal of the natural resting place will 
send scores of mosquitoes into the nearby houses. It is not yet known whether 
the malaria-conveying Anophelines, when numerous in a shaded area containing 
tall grass, brush, and trees, will bite malarial persons resting in such places 
in the daytime, and remain in the vicinity long enough to transmit malaria 
to other persons that may come to rest, or sleep, in the same place in the day- 
time during the following weeks. It would seem as though this does take 
place, and if so, it may have an important bearing on the status of malaria 
in the Canal Zone. 



1 The above list does not include the A. Crucians, the most common carrier in Flor- 
ida (Byrd) and Louisiana (Mitchell), and probably other southern states where mos- 
quitoes have not been very closely studied. 



ETIOLOGY THE MALARIA-CARRYING MOSQUITOES. 



53 



In even the temperate climates it is a common occurrence to see 
Anophelines flying around dark corners of rooms and in closets, dur- 
ing the daytime, and they will under some circumstances feed, but 
their doing so must be an unusual occurrence, or those observing 
faithfully the sanitary laws for the prevention of malarial infec- 




Fig. 15. — Resting position of Anopheles maculipennis, Meigen; enlarged. (After 

Howard.) 

tion would not remain as uniformly free frOm the disease as they 
do. 

The consensus of opinion is that in the more temperate climates 
day-feeding is very unusual, that they may feed at all times in 
certain tropical countries, but that in even these they are naturally 
nocturnal feeders. 

The resting position of the Anopht lints is characteristic (Fig. 15), 




Fig. 16. — Resting position of Anopheles and Culex. (After Howard; from sketch by 

Waterhouse.) 

and of itself is sufficient to differentiate them from other groups. 
Its body, instead of assuming a parallel position with the resting 
surface, is seen to be at an angle of 45° to it. This is caused by 
the proboscis, head, thorax, and abdomen forming a straight line; 



54 



MALARIA. 



while in the Culex, the proboscis, head, and thorax form an angle 
with the abdomen (Fig. 16). 

There has been a great difference of opinion expressed as to 
the distance that the Anophelines will fly. The question is an im- 
portant one when considering the feasibility, in a given district, of 
destroying the local breeding places, thus maintaining a sanitary 




Pi g 17 — Anopheles argyrotarsis, Desvoidy ; adult female ; enlarged. 
(After Howard.) 

malaria area. While such destruction will always be followed by 
results, it is obvious that the same success will not attend the move- 
ment, if there are outside this area breeding places from which 
the mosquitoes will migrate. Craig states, from personal observa- 
tion in the Philippine Islands, that he is satisfied that Anophelines 
will fly from two to two and a half miles in search of food. Ob- 
servations recently carried on by Le Prince in the Canal Zone,- 



ETIOLOGY THE MALARIA-CARRYING MOSQUITOES. 



55 



Panama, show that certain anophelines will fly long distances, and 
he has captured marked specimens 6,000 feet from the point of 
their liberation, while several specimens stained near their breed- 
ing places were found in the same localities two weeks later. It 
has been stated that the insect will seek, for the deposit of her 
eggs, the same breeding place from which she originated, and that 
this choice of breeding place will be sought for several succeeding 
generations. 

Mosquitoes are capable of hibernation in both the larvae or 
winged state. Only the female winged insect is capable of doing 
this, the adult males dying early in the cold months. 




Fig. 18. — Female of Anopheles punctipennis, Say; enlarged. 
(After Howard.) 



GENERAL DESCRIPTION OF THE ANOPHELINES. 

A lengthy description of mosquitoes and their biology, while of 
interest to the zoologist, is not of practical value to the general 
practitioner, and for this reason we shall not go extensively into 
details, but will pass the subject with a few statements concerning 



56 MALARIA. 

the chief points of interest in the anatomy of the Anophelines as 
differentiating them from other mosquitoes. The chief points of 
anatomical interest are the proboscis, the palpi, the antennas, and 
the salivary glands. 

The proboscis is a hollow tube representing the insect's mouth, 
which allows her to draw the blood into her stomach during the 
biting process. The palpi, two in number, are situated on each side 
of the proboscis, and in the female are of equal length, or nearly 
so, to the proboscis, this being an important differential point in 
determining an AnopheUne from the Culex, in which they are very 




Fig. 19. — Male of Anopheles punctipennis, Say; from side; enlarged. 
(After Howard.) 

short. The antennas arise from a point on the head close to the 
palpi, and in the female, the only one capable of carrying the in- 
fection, can be differentiated from those of the harmless male by 
the difference in their appearance, those of the female having a few 
straight hairs of great relative length, while on those of the male 
insect the growth of hair is much heavier and broadens into plumes, 
making a pretty and definite picture under a low-power objective, 
and also discernible to the naked eye. The salivary glands are of 
especial interest, as it is in them that the sporozoites are lodged with 
which the mosquito inoculates man with malaria. These, two in 
number, are connected with the proboscis, at the base of which are 
situated voluntary muscles that allow the insect to inject her saliva 
into man in the biting process. 



ETIOLOGY THE MALARIA-CARRYING MOSQUITOES. 



57 



DEVELOPMENT OF THE MALARIAL PLASMODIA IN THE 

MOSQUITO. 

This has been briefly referred to in the preceding chapter. The 
various changes of the parasite in its evolution within the body of 
the mosquito have been carefully observed by many investigators, 
and the following detailed description is taken verbatim from a 
recent work by Craig, who has kindly given his consent. The ob- 
servations, he states, are derived from the studies of Schaudinn, 




Fig. 20. 



-Anopheles crucians, Wiedemann; adult female: enlarged. The most common 
species found in the southern states. (After Howard.) 



Grassi, Bastianelli, Bignami, together with his own, and is probably 
the most complete description that has been written : 

Previous to the formation of the microgametes, the microgametocytes un- 
dergo certain changes which are of interest. The nucleus gives off a large 
amount of chromatin, which becomes arranged about the periphery of the 
organism, and which enters into the formation of the thread-like microgametes. 
It would appear that this chromatin is taken up by the microgametes just 
before the latter emerge from the body of the microgametocyte, for in stained 
specimens it is but seldom that any chromatin is observed in the residual body 
immediately after the appearance of the microgametes. 



58 



MALARIA. 



The only change observed in the macrogamete prior to fertilization concerns 
the nucleus, a portion of the substance of which is claimed by Schaudinn to 
be eliminated. 

When fertilization occurs, the microgamete penetrating the macrogamete, 
the chromatin of the former constitutes a pronucleus which fuses with the 
female pronucleus of the macrogamete, and a fertilization spindle is thus 
formed, which is often very well defined in properly prepared specimens. The 
organism resulting from the union of the micro- and macrogamete, or the 
zygote, does not encyst, but develops into an elongated vermicule or ookinete. 




Fig. 21. — Male and female of Anopheles maculipennis, Meigen. (After Howard.) 



This body is somewhat oval in shape, the anterior extremity being very narrow 
and pointed, while the posterior extremity is broad and rounded in appear- 
ance. The nucleus is situated a little posterior to the middle of the body and 
is composed very largely of chromatin, which takes a deep-red stain with 
Wright's method of staining. The pigment is collected in a loosely arranged 
mass near the posterior extremity and later in the development of the ookinete 
may be extruded or may be retained until the formation of the sporozoites, 
when it is liberated together with a portion of residual protoplasm. The 
movements of the ookinete are very active, consisting of contractions of the 



ETIOLOGY THE MALARIA-CARRYING MOSQUITOES. 59 

body and of a rapid progressive motion, gliding in character, no satisfactory 
explanation of which has as yet been given. Schewiakoff believes that the 
gliding progressive motion is due to the secretion and extrusion of a gelatinous 
thread which pushes the organism forward as it is formed, while Crawley 
thinks that the motion is due to wave-like contractions of the protoplasm. 
However the motion is produced, it enables the ookinete to force its way 
through the epithelial lining of the mosquito's stomach and reach that por- 
tion of the stomach wall immediately beneath the epithelial lining, where 
it rests and the oocyst is formed. When it reaches this locality the ookinete 
becomes spherical in shape and secretes a delicate covering membrane, con- 
tinuing to grow until it projects from the stomach wall toward the body 
cavity of the insect. 

The nucleus divides, and each daughter-nucleus is surrounded by a portion 
of protoplasm, forming the sporoblasts; the sporozoites are developed within 
the sporoblasts by the repeated division of the nucleus of each sporoblast, the 
small nuclei thus produced accumulating upon the surface of the sporoblast 
and forming delicate protoplasmic prolongations, each consisting of a little 
protoplasm and a clump of chromatin, eventually forming the sporozoites. 
When development is complete, the cyst is filled with a multitude of sporo- 
zoites together with some residual protoplasm, and in many instances con- 
siderable pigment. When the cyst ruptures, the sporozoites are liberated in 
the body cavity of the insect and are carried by the blood to the salivary glands, 
from which they pass down the proboscis to the blood of man when the mos- 
quito bites. The sporozoites are actively motile, spindle-shaped, and measure 
about 14 microns in length. 

The time consumed in sporogony has been variously estimated at from 10 
to 14 days, the average being 10 to 12 days. It varies, in all probability, with 
each species- of plasmodium, but never exceeds 14 days. 

The fertilization of the macrogamete by the microgamete, first observed in 
human malaria by MacCallum, has been observed by Koch, in Africa, and by 
Ashburn and myself, in the Philippine Islands, in blood from malarial cases 
removed for some time from the body. 

To those who are interested in tracing the development of the malarial 
Plasmodia within the mosquito, the following description, arranged in periods 
of time may prove useful : 

First and Second Days After Ingestion of Malarial Blood. — The fusi- 
form and spindle-shaped ookinetes penetrate the epithelial lining of the insect's 
stomach and reach the muscular layer, where they encyst and form the oocyst. 
In stained specimens the ookinete presents at or near the center a deep-red 
chromatin mass, representing the nucleus, the chromatin being in the form 
of short, very delicate threads or granules. The pigment is collected in a 
dense clump at the posterior end or is distributed throughout the protoplasm: 
the protoplasm contains numerous vacuoles and stains a light-blue color. The 
oocyst at the end of two days is about the size of a red blood corpuscle, con- 
tains considerable pigment distributed throughout the protoplasm, and the 
chromatin is found in small granules or in minute irregular masses, col- 
lected toward the center of the organism. 

Third and Fourth Days. — During the third and fourth days the oocyst 



60 MALARIA. 

increases to twice its original size, and develops a well-marked cyst wall. The 
pigment is not increased in amount, and is collected in small masses; the 
protoplasm is vacuolated, and the chromatin is distributed throughout it in 
fine granules or delicate threads. 

Fifth and Sixth Days. — At the end of the sixth day the cyst has increased 
very greatly in size, measuring from 35 to 75 microns in diameter, and projects 
from the wall of the stomach outward toward the body cavity of the insect. 
The protoplasm appears granular, and large, very refractive spherical bodies 
may be distinguished within it, the sporoblasts. The pigment has not increased 
in amount and, owing to the great increase in size of the organism, appears 
to have greatly diminished; in some instances the cyst, at this stage, is devoid 
of pigment. The chromatin is collected in the sporoblasts and stains red, 
while the protoplasm stains a very pale blue. 

Seventh to Eighth Days. — Under favorable circumstances, and in some spe- 
cies of Anophelina, the cysts have attained their full growth in eight days. 
At this time a well-marked double-outlined membrane surrounds them, which 
is perfectly smooth in contour; the sporoblasts form common centers from 
which radiate multitudes of delicate, elongated, spindle-shaped, or thread-like 
bodies, the sporozoites. The sporozoites appear to originate from the outer 
layers of the sporoblasts, each sporozoite being attached by its inner extremity 
to a small portion of the residual protoplasm of the sporoblast. When isolated 
and stained each sporozoite measures from 12 to 14 microns in length, and 
contains one or more masses of chromatin imbedded in the light-blue pro- 
toplasm. When fully developed the sporozoites become detached from the 
sporoblasts, and the cyst is then observed to be filled with multitudes of these 
delicate filamentous organisms. 

The above description applies to the tertian estivo-autumnal plasmodium, 
but practically the same appearances are observed in the mosquito cycle of the 
benign tertian and quartan plasmodia. It should be remembered that in any 
one insect all of the plasmodia are not in the same stage of development at 
the same time, some being more advanced than others, but the periods as 
given are true for the vast majority of estivo-autumnal plasmodia, in most 
species of Anophelina. Unless the temperature be suitable, the development 
may be delayed to 12 or even 14 days, and in Myzomyia funesta, a very com- 
mon malaria carrier, the cycle of development at 80° F. always takes 12 days. 

After the sporozoites are liberated into the body cavity of the insect by 
the rupture of the cyst wall, they may be observed in fluid from any portion 
of the body of the insect, and if the cells of the salivary glands be examined 
numerous sporozoites will be seen within them, as well as within the salivary 
ducts. 



CHAPTER IV. 
ETIOLOGY— OTHER FACTORS. 

There are many conditions that in an indirect manner favor the 
endemicity or epidemicity of the disease, and while two factors, cer- 
tain mosquitoes and malaria-infected man, are necessary for the 
production of it, it is well to bear in mind all those conditions that, 
in an indirect manner, favor the spread and perpetuation of the 
infection. 

PREDISPOSING FACTORS. 

Climate. — Heat and moisture being necessary for the breeding of 
mosquitoes, it stands to reason that malarial infections will be more 
common in warm climates than in the temperate ones. Not only 
are malarial infections more common in tropical and subtropical 
climates, but the disease is more virulent in these countries. Malig- 
nant infections will seldom if ever be seen in the temperate regions, 
while the estivo-autumnal infections are often the preponderating 
ones in warm countries. The parasite will not develop in the 
mosquito where the mean temperature is below 60° F., and there 
are many species of mosquitoes in Avhich the parasite will not 
develop except at a temperature much higher than even this, so 
that, in sections of a country where the autumn or winter tempera- 
ture drops below this level, the mosquitoes that are infected be- 
come sterile and incapable of transmitting the disease, until a tem- 
perature of above 60° F. is maintained a sufficient time to allow 
the development of the sporozoites, after the mosquito becomes re- 
infected from some chronic gamete carrier. The body temperature 
of man is always at a sufficiently high point to allow^ the presence 
cf the sexual forms of the parasite, so that, in these communities 
where weather conditions are such through the winter months as 
to interfere with the development of the parasite in the mosquito, 
and the early warm months find the mosquito, though present, 
sterile, the sexual forms with which the insect becomes reinfected 
when biting man not being removed; after a certain period, rep- 

61 



62 MALARIA. 

resenting the time necessary for the development of the sporozoites 
in the mosquito, together with the period of incubation required for 
the disease to become manifest in man, the disease reappears. 

Deaderick states that Hirsch marks the northern boundary of 
malarial infections in the northern hemisphere as ranging from 45 
to 65 degrees north latitude, "the line starts from 55 N. on the 
western side of North America, sinks to 45 on its eastern side, rises 
to 63 or 64 on the western sides of the old worlds (Sweden and 
Finland), and runs across Northern Asia in about the latitude of 
55." All territory south of this line may be regarded as within 
the malarial zone, but there are many sections free from malarial 
infection, owing to the fact that the parasites are not present in the 
circulation of the inhabitants, and without that focus of infection, 
the mosquito is of course harmless. 

Altitude. — As a general rule, it may be said that high altitudes 
are not conducive to malarial infections. Climatic conditions are 
partially responsible for this, together with the fact that all high- 
lands naturally permit of drainage better than the lowlands, but 
there are, however, numerous exceptions to this rule, several ob- 
servers reporting the infection at high altitudes. A person suf- 
fering from a latent form of the disease will frequently suffer a 
relapse following his removal to a high altitude, and we have at 
the present time no satisfactory explanation for this. 

Rain. — Water being necessary for the creation of breeding places 
for the mosquito, it follows that rainy periods will later result in 
an exacerbation of the infection in a given community under 
favorable conditions for the transfer of the parasites from one host 
to the other. It is not infrequent, however, to have a heavy rain- 
fall result in the destruction of already formed breeding places, by 
fhishing them, clearing them of larvae. 

Season. — In most malarial countries the infection will gradually 
increase as the warm season advances, and the report of the De- 
partment of Sanitation of the Isthmian Canal Commission for 
1911, illustrates how it increases with the warm months. (See 
Table II.) 

This table shows a commencing rise in May, the maximum num- 
ber of cases occurring in June and July, followed by a steady de- 
cline during the succeeding months. 

The author has frequently observed that in the Southern states 
the infection often reaches the point of maximum intensity (nu- 



ETIOLOGY — OTHER FACTORS. 



63 



Months. 



TABLE II. 

HOSPITAL CASES OF MALARIA AMONG EMPLOYEES. 



January 
February 
Ma reli . . 
April . . . 
May . . . 
June . . . 
July . . . 
August 
September 
October . 
November 
December 
Total 



Discharged. 


Died. 




Annual 


Annual 








Total 


average 
per 


average 
per 










W. 


C. 


W. 


C. 




1,000 of 


1,000 of 






1 


1 




deaths. 


cases. 


180 


157 


339 


0.51 


86 


217 


166 


1 




384 


.24 


93 


239 


167 




1 


407 


.25 


102 


190 


138 


1 




329 


.25 


81 


4(31 


463 


1 


3 


928 


.99 


230 


756 


981 


4 


4 


1,745 


1.98 


432 


747 


1,226 


4 


4 


1,981 


2.01 


497 


39G 


506 


3 


2 


907 


1.21 


219 


322 


339 


3 




664 


.76 


168 


253 


249 


1 




503 


.24 


121 


199 


210 


4 


1 


414 


1.19 


99 


191 


193 


1 


1 


386 


.47 


91 


4,151 


4,795 


24 


17 


8,987 


.84 


184 



Number 
of em- 
ployees. 



47,348 
49,785 
47,935 
48,634 
48,496 
48,519 
47,801 
49,710 
47,400 
49,812 
50,420 
50,655 
48,876 



merically) late in the season, October, or even November. This 
is no doubt due to the slowly increasing number of gamete 
carriers resulting from indifferent treatment throughout the warm 
season, which results in a higher percentage of mosquitoes becom- 
ing infected as the season advances. It would be interesting to 
note the increasing percentage of infected mosquitoes as the season 
advances in a given community, where, owing to climatic condi- 
tions in the spring, they are sterile. As will be shown later, we 
cannot lay too much stress upon the significance of every additional 
gamete carrier in a community. 

Occupation. — With our knowledge concerning the transmission 
of the disease, it stands to reason that occupation is a predisposing 
factor, those working at night, subjected to the bites of infected 
mosquitoes, necessarily being in greater danger of becoming in- 
fected than those not so exposed. It is also probably true that any 
occupation which necessitates the disturbance, during the daytime, 
of underbrush, or any material which may harbor the resting in- 
sect, will, in those sections where the mosquito feeds in the daytime, 
predispose to infection. 

Race. — It has been claimed by some in the past that the dark- 
skinned races enjoy a greater degree of natural immunity to ma- 
larial infection than that possessed by the lighter-skinned races, 
but this view has been largely modified in more recent years. 
There is little question that a given number of negroes will not 
develop as many malarial infections as the same number of white 



64 MALARIA. 

men under similar conditions, but this is no doubt due to a cer- 
tain acquired immunity, attained in childhood. The mortality 
among negro children is appallingly high in some localities, and 
those that survive probably acquire a certain immunity — this will 
be discussed further in considering the immunity of the disease. 

Sex and age. — Sex has no apparent influence on the disease, the 
same ratio of males and females exposed will become infected. 
Deaderick gives the following table of sex distribution in a few 
localities : 

TABLE III. 

Males. Females. 

Stephensport 32 21 

Italy 312 327 

Alabama 585 451 

Italy 311 236 

Bulgaria 1,742 995 

Italy 268 147 

Greece 1,202 972 

Baltimore 493 121 

4,945 3,270 

While this table shows in the aggregate that more men than 
women were infected, it is probably due to the fact that, as a 
general rule, men are exposed to the infection to a greater degree 
than are women, and not to the fact that women possess any degree 
of immunity. 

Children are more often attacked than adults, and in them the 
infection is generally more severe. They seem to be more suscepti- 
ble to the poisons and do not possess the acquired immunity that 
older persons may obtain with long residence in malarial countries. 
Craig states that, from his observations in the Philippine Islands, 
while young children are more susceptible than older ones, in that 
country the adults suffer from the disease as much, or even more, 
than do the children. 

Effect of Improper Diet. — As any condition that will reduce the 
resisting powers of the individual favors malarial, as well as other 
infections, it is but natural that improper food will in some in- 
stances precipitate attacks. It is not probable that this is an im- 
portant predisposing factor in this country, but there are sections 
of the world where it is a very serious problem. Leslie, in speak- 
ing of conditions in India, states that : 

In the towns, in India as in other countries, there are numbers of people 
who lead a hand-to-mouth existence; ill-housed, ill-clad, and ill-fed, they pick 
up a precarious ln r elihood in the unskilled labor market. Such people have 



ETIOLOGY OTHER FACTORS. 65 

unsuitable food at the best of times, and they have no savings, so that, when 
anything occurs to check the demand for such work as they can do, the scanty 
coarse food becomes scantier and coarser and they and those dependent on 
them offer little resistance to malarial infection and readily succumb to its 
effects. Analogous conditions, as pointed out by Christophers and Bentley, may 
be artificially produced in any area in which Anopheles breed, when large 
numbers of laborers are collected in it under bad hygienic conditions. The 
majority of such laborers are free from infection, but are highly susceptible 
to it, a few are infected, and all are dependent on their daily labor for their 
daily bread. Infection spreads and with it the inability to earn money to 
pay for sufficient food, privation added to malaria determines a severe attack, 
attacks are repeated, and here again the disease is a very fatal one. 

Surgical Operations. — These will often wake up a latent infec- 
tion, while any pathological condition that lowers the resistance of 
the individual will increase the likelihood of original infection; 
and it is a common occurrence to see a woman in the lying-in period 
develop symptoms which may arouse suspicions of sepsis, but which 
in reality are due to a recurrent malarial infection. An examina- 
tion of the blood of such individuals is of paramount importance, 
for the purpose of demonstrating that the infection is of malarial 
origin and not due to puerperal sepsis. 

Effect of Residence. — The period of time that will elapse before 
a newcomer in a malarial region will become infected is governed 
by many conditions. The prevalence of the disease, and the pro- 
phylactic measures taken by the individual necessarily enter largely 
into the matter. There are many sections of the world where ma- 
laria is endemic, but where individuals, observing proper precau- 
tions, have lived for years without ever becoming infected. Change 
of residence will often bring on an attack when the disease is latent, 
as mentioned in discussing the effect of altitude. 

CONGENITAL MALARIA. 

It has been a very much debated question as to whether the fetus 
in utero could become infected through the placenta, if the mother 
developed the disease during pregnancy. From a careful review 
of the literature together with personal observation, the author is 
of the opinion that the general evidence is arrayed against this 
theory, although it cannot be regarded as an absolutely set- 
tled question at this time. In all of the cases reported, in which it 
was claimed that the infection was prenatal, it was almost impos- 
sible to absolutely exclude postnatal infection, which of course 



66 MALARIA. 

renders such evidence of prenatal infection as valueless. Craig 
cites the negative findings of Bignami, Bastianelli, Caccini, Schau- 
dinn, and Sereni. The author has made frequent examinations im- 
mediately after birth of several infants, whose mothers, during the 
last few weeks of pregnancy, he had been called upon to treat for 
malaria, demonstrating, in the blood of the mother, the parasites. 
These examinations included several estivo-autumnal and benign 
tertian infections, and one case of the quartan type, but he was 
unable in a single instance to demonstrate the parasites in any of 
the new-born, although in not a few of them at birth, preceding, 
and following it, the parasites were detected in the blood of the 
mother. 

PATHOGENESIS. 

There have been in the past many theories as to what produced 
the fever in malarial infections, but without going into a general 
discussion of these, it may be stated that it is now universally agreed 
that the cause of the fever is the result of the liberation of a toxin, 
formed during the intracorpuscular growth of the plasmodia, which 
takes place with the sporulation of the organism. 

PERIOD OF INCUBATION. 

Ross and Thomson have shown that the number of parasites nec- 
essary to produce clinical symptoms is about 2,000,000,000. It 
would therefore seem that the period of incubation would be de- 
termined largely by the number of sporozoites injected by the in- 
fected mosquito, but as a matter of fact, there is a certain uniformity 
in the period of incubation, depending on the type of the infection. 
In Table IV, which the author tabulated from a history of inocula- 
tions collected from the literature by Ross, is shown the period of 
incubation after mosquito inoculation; the complete history 
of each inoculation, which is given by this author in his recent work 
on The Prevention of Malaria, is omitted from these pages, owing 
to the space required to reproduce it, for, while of certain interest, 
it is only desired here to show the actual period of incubation, 
which is of considerable importance to the physician. 

This tabulation shows that the period of incubation in the benign 
tertian varies from 8 to 25 days : the single case of quartan, show- 
ing an incubation period of 11 days; while the estivo-autumnal 
infections show a period varying from 10 to 35 days. 





ETIOLOGY OTHER FACTORS. 67 




TABLE IV. 




Observer. 


Spec 


ies inoculated. 


Period of incubation. 


Bignami. 


(1898) 


Est.-Aut. 


(type?). 


35 days. 


Bastianelli, Bignam 


, 








and Grassi. 


(1898) 








Ibid. 


(1898) 


Tertian. 




20 days. 


Ibid. 


(1898) 


Tertian. 




19 days. 


Manson. 


(1900) 


Est.-Aut. 


(type?). 


34 days. 


Rees. 


(1900) 


Tertian. 




15 days. 


Fearnside. 


(1901) 


Tertian. 




About 14 days. 


Ibid. 




Tertian. 




Uncertain. 


Ibid. 




Tertian. 




21 days. 


Ibid. 




Tertian. 




15 days. 


Ibid. 




Tertian'. 




25 days. 


Ibid. 




Tertian. 




12 days. 


Buchanan. 


(1903) 


Tertian. 




16 days. 


Ibid. 




Est.-Aut. 


(type?). 


20 days. 


Ibid. 




Est.-Aut. 


(type?). 


19 days. 


Ibid. 




Est.-Aut. 


(type?). 


12 days. 


Ibid. 




Est.-Aut. 


(type?). 


19 days. 


Ibid. 




Est.-Aut. 


(type?). 


19 days. 


Ibid. 




Quartan. 




11 days. 


Ibid. 




Tertian. 




14 days. 


Ibid. 




.Tertian. 




18 days. 


Ibid. 




; Tertian. 




8 days. 


Schuffner. 


(1902) 


Tertian. 




11 days. 


Ibid. 




Tertian. 




17 days. 


Ibid. 




| Tertian. 




17 days. 


Jancso. 


(1905) 


Est.-Aut. 


(type?). 


16 days. 


Ibid. 




1 Tertian. 




15 days. 


Ibid. 




lEst.-Aut. 


(type?). 


12 days. 


Ibid. 




Est.-Aut. 


(type?). 


10 days. 


Ibid. 




Est.-Aut. 


(type?). 


10 days. 


Ibid. 




Est.-Aut. 


(type?). 


After 14 days crescents ii 
blood. 


Ibid. 




Est.-Aut. 


(type?). 


12 days. 


Ibid. 




. Est.-Aut. 


(type?). 


14 days. 


Ibid. 




Est.-Aut. 


(type?). 


11 days. 


Ibid. 




Est.-Aut. 


(type?). 


11 days. 



FACTOR IN INTENSE INFECTIONS. 

Christophers recently carried on some interesting experiments 
showing the factor which determines the intensity of an infection. 
He found that, if he fed mosquitoes (Culex) with the blood of spar- 
rows containing but a few gametes, the midgut of such mosqui- 
toes on dissection showed but a few zygotes, and that, when the 
zygotes were allowed to mature and reach the salivary glands of 
the insect, there were but a few of the salivary cells infected and 
that those that were did not contain sporozoites in large numbers. 
On the other hand, mosquitoes fed with blood from the sparrow 
containing numerous gametes showed on dissection large numbers 



68 MALARIA. 

of zygotes in the midgut, and on maturing, the sporozoites were 
found in immense numbers in all of the salivary cells. In the con- 
tinuation of this line of research, he found that, by using a certain 
number of heavily infected mosquitoes, the resulting infections 
were sufficiently severe to produce death in every instance, and 
that in all cases the usual period of incubation, consisting of nine 
days in the moderate infections, was reduced to five days. In using 
equal numbers of mosquitoes that were scantily infected, or even 
by increasing the number, he was unable to produce a severe in- 
fection, nor was he able to reduce the period of incubation. He 
concluded that "The amount of infection carried by mosquitoes 
then depends on the number of zygotes which develop in the mid- 
gut, and the number of these in turn depends upon the number 
of gametes in the blood of the sparrow by which the mosquito 
became infected. It is easy, therefore, to see that in malaria every- 
thing may depend upon the existence of heavy gamete carriers; 
and if these are present, upon the number of Anopheles. Other- 
wise, the relation of number of Anopheles to. the amount of fever 
will not hold good." 

A few years ago the author saw in a village, in which malaria 
was endemic, a number of very serious infections. An examination 
of the blood of practically all of the inhabitants showed that there 
were two individuals very heavily infected with crescents. Under 
appropriate treatment these individuals were freed of these forms, 
and he has since seen no heavy infections in this place, and is 
satisfied that the severe cases that previously occurred were in- 
fected by mosquitoes that had been biting and feeding on these 
heavily infected individuals. Wherever, therefore, heavy infec- 
tions are occurring in a community where such are unusual, it is 
well to look for the individual source of infection, and when this 
is done and the carriers put on appropriate treatment, it will be 
followed by an absence of such heavy infections. 

IMMUNITY. 

The question of persons being immune to the malarial infections 
is one that has been discussed pro and con for many years, and 
there is no doubt that individuals do develop a certain immunity 
after living for some time in a malarial country and having had 
repeated attacks. A study of latent carriers in childhood will 
show the large percentage of individuals who must have been 



ETIOLOGY — OTHER FACTORS. 



69 



infected before reaching adult life. Panse in the examination 
of 2,227 natives of East Africa found the following percentage of 
latent carriers: 

TABLE V. 



Age. 



Under y 2 year 

Between V 2 and 1 year 

1 year old 

2 years old 

3 years old 

Between 4 and 5 

Between 6 and 7 

Half grown children. . . 
Adults 



No. examined. 


No. infected. 


Per cent. 


16 


6 


37.50 


9 


6 


66.60 


25 


22 


88.00 


20 


17 


85.00 


28 


25 


89.20 


48 


34 


70.80 


84 


52 


61.90 


314 


125 


39.40 


1,683 


258 


15.30 



Many other observers have reported similar results, so that in 
those countries showing a high malarial index among the infants 
and young children, and slowly declining as adolescence is reached, 
it is reasonable to infer that a certain amount of immunity is 
acquired by repeated infections. On the other hand, there are evi- 
dently some people that in spite of heavy and repeated infections 
are unable to secure any immunity. Craig examined the blood of 
147 children and 45 adults in the Philippine Islands with the fol- 
lowing results: 

TABLE VI. 



Age. 


No. examined. 


No. infected. 


Per cent. 


1 to 5 years 

5 to 10 years 


40 
54 
53 
45 


30 
20 
13 

28 


72.50 
37 00 


10 to 15 years 


24 50 


Adults 


62 20 







It will be seen by the above that while the percentage of infections 
decreased from the fifth to the fifteenth years from 72.50 to 24.50 
that the percentage in adults rose to the high figure of 62.20. Craig, 
in discussing these findings, states that he is unable to explain why 
the rate, although decreasing as the age advances up to young 
adult life, advances so markedly from then on. He is of the opinion 
that the examination of larger numbers of adults in that country 
would probably reduce the percentage of infections as shown in his 
examinations, but considers it very evident that the Filipino de- 
velops little immunity to the infection in spite of repeated attacks. 



70 



MALARIA. 



The above observations of infections in adults has been confirmed 
by Plehn in West Africa. He examined 84 children and 43 adults 
with the following results : 

TABLE VII. 



Age. 


No. examined. 


No. infected. 


Per cent. 


Under 2 years 

Between 2 and 5 

Between 5 and 10 

Adults 


18 
26 
40 
43 


17 
24 
34 

26 


94 
92 

85 
60 







It may be concluded that, while certain people acquire an im- 
munity following repeated attacks, there are certain sections where 
the inhabitants do not obtain such. Manson speaks of the natives 
of Italy, Corsica, Greece, and Turkey failing to derive any im- 
munity in spite of repeated infections. 

On the other hand, there are certain races that appear to enjoy 
a certain natural immunity, such as the Chinese and Malays. Many 
writers have questioned the immunity said to be possessed by our 
negroes, but the statistics given in the report of the Surgeon Gen- 
eral of the United States Army for the year 1911 (Table VIII) in- 
dicate that this race possesses a marked immunity, which is, 
however, probably acquired in early life following repeated infec- 
tions. 

ENDEMIC INDEX. 

It has been usual in the past to consider the malarial index of 
a community largely in accordance with the percentage of splenic 
enlargements found among the inhabitants. This has to be dis- 
carded in those sections where kala azar is also present, .owing to 
the marked splenomegalia that exists in the latter infection, and 
which until a short time ago was considered to be nothing but a 
manifestation of malaria. With the knowledge that kala azar is a 
disease per se, it is plainly evident that, inasmuch as it is accom- 
panied by splenomegalia, this system, as a guide to the malarial 
index, was on a false basis wherever both the diseases prevail. 
Table IX prepared by Stephens and Christophers illustrates the 
fallacy of depending on the spleen rate for the index of malaria, the 
figures being based on the spleen enlargement rate and the parasite 
rate : 



ETIOLOGY OTHER FACTORS. 



71 



-pa.ioic>o 



■9} RAY 



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CT^Ttmoi oocor-i ooooo co m in co r-i 



•pa.ioioo 



> 5 



•9»™IA\ 



•isjoj, 



o o . 
'So'? 



•paaojoo 



■^PIAl 



T^o^ 



•p9J OI 00 



•a^T^AV 



co co cc to i> 

Tl< X ■<* <M O 



(Mt-HffiO 
OlflOON 



i-H t-CO (OH <M 
r-liM CMCOIO 



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t- CT. <N TF C<! CO CO O rH t- 

LO OJ tH ^_ CO COffiCWM 

rj<" d I-OCV r-i i-i <M* r-i H 
r-l (M CM <N t)< 



'CO CO CO 05 O t- 
IO COO CO <M (M 
r-i CO CO CO O O* 

ih <m (M co m 



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PHO 

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CCO % r-O 
C-.CC-. T O! OS 



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CCO~-~r-IOCOC £ r-i C O O O 

os c o =8 o cs c <r. c. oa t oa cs a a-, o 






i 1 MALARIA. 

TABLE IX. 

Locality. Spleen rate. Parasite rate. 

Calcutta 0.0 0.0 

Jalpaiguri — 

Bustee children 27.0 16.1 

School children 14.7 0.0 

Babu children 14.2 0.0 

Mainaguri 74.0 25.0 

Rungamutty 83.0 43.6 

Sam Sing 7.1 16.0 

Kurseong 1 0.0 0.0 

Kurseong 11 0.2 0.0 

Eoss considers that "there is probably only one really accurate 
method by which we can determine the degree of malaria in a given 
locality, and that is by ascertaining the average time in which a 
newcomer becomes infected." Deaderick considers that the most 
accurate method to determine the index is to examine a number of 
children, the percentage of gamete carriers giving the true index. 
Both of these methods are open to objection. The first will be gov- 
erned almost entirely by the precautions observed by the newcomer, 
and it has already been shown that in some communities gamete 
carriers may be equally as numerous among adults as in children, 
and in some exceptional instances even more so. The only satis- 
factory and certain manner, therefore, to determine the index in 
a given community, is to examine the blood of a large number of 
inhabitants of all ages. 

OLD-TIME THEORIES CONCERNING TRANSMISSION. 

Any discussion of the etiology of malaria is not complete without 
a passing reference to the various exploded theories concerning the 
transmission of the disease. The full value of the discovery that 
the mosquito is the carrier of the infection lies in the fact that we 
also know that it is the only method by which the disease can be 
contracted. The very nature of practically all these old theories is 
now seen to be coincident with the established etiological factor. 
Thus the night air, which was held to be so dangerous in malarial 
countries, is now known to be harmless provided it does not contain 
the hungry mosquito intent on a meal of fresh blood. Working in 
swamps, the presence of "miasmas" or decaying vegetable matter, 
going into the water in the evening hours, and many other more 
or less popular theories, held in the past, are now seen to be all con- 
comitant with the presence of the mosquito, because it is in such 
places that they are found. Probably the most popular theory, and 
one that held favor for a long period previous to the discovery by 



ETIOLOGY OTHER FACTORS. 73 

Ross, was that the disease was contracted during the upheaval of 
soil by the liberation of toxins. It is not hard to convince the most 
skeptical at the present time that the disturbance of the soil results 
in the creation of breeding places for the mosquito, and that only 
in this manner is such soil disturbance a factor in the etiology of 
the malarial fevers. The segregation of labor at points where 
extensive earth-disturbing projects are under way often furnishes, 
in the form of chronic gamete carriers among such laborers, the 
other necessary factor for an epidemic of the disease, and so it be- 
comes rampant, as a result of these two etiological factors: con- 
ditions favoring the breeding of mosquitoes, and the presence of 
gametes in the circulation of man. 

CULTIVATION OF MALARIAL PLASMODIA. 

Many investigators have attempted the cultivation of plasmodia 
in vitro since the discovery of the parasite by Laveran, but the 
results have been uniformly negative until very recently. In 1911 
Bass 1 first announced successful cultivation of Plasmodia vivax, 
Plasmodia malarial, and Plasmodia falciparum*. Detailed technic 
was not given at that time. 

In October, 1912, Bass and Johns 2 published a report of suc- 
cessful cultivation of malarial plasmodia from the blood of twenty- 
nine cases of estivo-autumnal malaria and six cases of tertian in 
Panama. 

In this communication the technic was given in the minutest 
detail as follows : 

TECHNIC. 

Apparatus and Material. — The apparatus and material necessary for the 
cultivation of one generation only of parasites are as follows : 

1. Syringe and needle. We use a twenty cubic centimeter all glass syringe 
with coarse needle. The latter is necessary to avoid strong capillary force 
and strong suction which so alter the host cells (or parasites), that the para- 
sites often die in a short time. The large needle is also desirable to avoid 
leaking and bubbling of air into the syringe and to facilitate taking blood 
into and expelling it from the syringe. 

2. Defibrinating tube. Tubes one inch in diameter and of whatever length 
will be accommodated by the centrifuge (if a centrifuge is to be used) are 
appropriate. The tube is plugged with a cotton plug having a glass rod 
running through it and extending to the bottom. We have used with equal 



1 Jour. A. M. A.. Vol. LVII, No. 19, p. 1534. 
2 Jour. Experimental Medicine, Vol. XVI, No. 4. 



74 MALARIA. 

satisfaction a glass tube in place of the rod. To this is attached the needle 
by means of a. short piece of rubber tubing. The blood is collected directly 
into the defibrinating tube by sticking the needle into an infected vein. 

3. Culture tubes one-half by five inches. 

4. Graduated pipette, one cubic centimeter, graduated in hundredths. 

5. Dextrose (Merck's), 50 per cent solution in water. 

6. Capillary pipettes and rubber bulb. Three to four-sixteenths of an inch 
glass tubing is the proper size from which to make these pipettes. The 
capillary tube should be rather large. Fine capillaries are destructive to 
malarial plasmodia. The large end of these pipettes should be plugged with 
cotton before sterilizing. 

7. Incubator regulated to a temperature of 40° C. 

The following additional apparatus will be required if more than one 
generation of parasites is to be grown, or if it is desired to avoid the dead 
parasites which are present in the deeper layers of cultures containing a thick 
column of cells : 

8. Centrifuge. Speed, 800 to 2,000 revolutions per minute. 

9. Culture tubes one-half by five inches, with flat bottom or with disk 
of pure white filter paper supported one-half inch from the bottom of the 
tube by a piece of glass tubing. The latter should be cut straight across 
and fairly smooth on the upper end and should fit the culture tube closely. 

10. Plain pipettes, capacity five to twenty cubic centimeters, with rubber 
tube two feet long, mouth piece, and pinch cock. These pipettes are plugged 
before sterilizing and are used but once on account of the difficulty of clean- 
ing them. 

Technic for Cultivating One Generation Only. — Blood is collected from 
the patient's vein at the bend of the elbow. If drawn with the syringe it 
is expelled directly into the defibrinating tube. The latter should be tilted 
to one side and care should be taken to avoid unnecessary exposure of the 
blood to the air. In either case, one-tenth of a cubic centimeter of the 50 
per cent solution of dextrose for each ten cubic centimeters of blood to be 
taken is placed in the defibrinating tube before the blood is drawn. De- 
fibrination is effected by gently stirring or whipping with the rod or tube 
which extends through the cotton plug. The whipping in of air, causing 
bubbles, must be avoided. The plug and rod may now be replaced by a 
plug from another tube of the same size. 

The defibrinated dextrose blood may be transferred to other tubes or in- 
cubated in - the original tube. In any event the column of blood must be 
one to two inches deep. This gives a column of serum one-half to one inch 
deep above the cells and parasites when the latter have settled. Supernatant 
serum more than one inch deep has no advantage. When this is less than 
one-half of an inch deep the parasites often die before segmentation occurs. 
We have occasionally seen perfect segmentation, however, under one-fourth 
of an inch of serum. 

The parasites live and develop at the top of the column of precipitated 
cells in a layer varying in thickness from one-fiftieth to one-twentieth of 
an inch. All parasites beneath this layer die in from two to twenty hours; 
the time is dependent upon factors which we have not determined. Some 



ETIOLOGY — OTHER FACTORS. 75 

grow considerably before tbey die and we have occasionally seen small rings 
attain over half the full adult size under these circumstances. When para- 
sites die in these deep cells the central clear space in the small ring closes, 
or if the parasite is older the irregular projections, pseudopodia, are with- 
drawn. If pigment is present, it loses its motility. The protoplasm gradu- 
ally shrinks, losing its staining reaction, and finally only the nuclear chro- 
matin granule remains, and this also stains poorly. In the instance of very 
small parasites often the red blood cell shows little or no evidence of the 
previous presence of the parasite. 

The parasites in the thin layer at the top of the column of cells develop 
and may be examined at any time by drawing a small quantity of cells from 
this layer by means of a capillary pipette. Some considerable practice is 
required in order to do this without drawing cells and dead parasites from 
just below this layer. The pipette may be passed through a flame to sterilize 
it on the outside, but it must be allowed to cool thoroughly before it is 
used, since, in our experience, a temperature of 45° to 50° C. kills the para- 
sites in a very short time. 

Such a temperature also alters the red blood cells in some way so that 
they are rendered permeable to the surrounding serum, and this effect is 
destructive to the parasites. Great care must be taken in handling tubes 
containing cultures to keep them in the upright position. Tilting to the 
side results in burying and killing the living parasites in the thin layer 
at the top of the cells which have settled to the bottom of the tube. 

Technic for Cultivating More than One Generation. — If more than one 
generation of plasmodia is to be cultivated, it is necessary to remove the 
leucocytes when the culture is made in order to avoid destruction of the 
parasites by them at the time of segmentation. The infected blood from 
the patient is centrifugalized sufficiently to force the leucocytes to the surface 
of the cells. The length of time necessary to centrifugalize varies with the 
speed, length of arm, etc., of the particular centrifuge used and should be 
determined by experiment. Unnecessary centrifugalization should be' avoided. 

The supernatant serum is drawn off and put in culture tubes. The column 
of serum in each should be one-half to one inch deep. Cells and plasmodia 
are carefully drawn from about the middle of the centrifugalized cells and 
planted at the bottom of the serum in the culture tubes. Flat bottom tubes 
are an advantage. One to two-tenths of a cubic centimeter of cells in a 
half-inch tube make the thickest layer in which it is possible to get a homo- 
geneous growth of parasites. We have been able to secure growth of all the 
parasites in about twice this quantity of cells in a half-inch tube by em- 
ploying tubes with a paper shelf suspended in them. They are filled with 
serum to at least half an inch above the level of the support for the paper 
disk. The disk is then carefully tucked in place, after which the cells are 
placed on it. 

We have obtained even more satisfactory results with tubes filled one-half 
inch deep, or more, with freshly prepared human plasma. These are con- 
veniently prepared by placing one-half to one inch of blood, immediately 
after it is drawn, in culture tubes and centrifugalizing to throw the cells 
to the bottom before coagulation takes place. By continuing centrifugaliza- 



76 MALARIA. 

tion until after coagulation occurs, a flatter surface is secured for the plasma 
than if it is discontinued before this time. In such plasma prepared tubes 
one-half inch or more of serum is placed and then cells and parasites from 
the centrifugalized and defibrinated dextrose blood are carefully distributed 
over the surface of the plasma. We have sometimes obtained in these tubes 
a layer of live parasites approximately one-tenth of an inch thick. 

Parasites in such leucocyte-free cultures develop, segment, and most of 
the merozoites enter new red blood cells. These young parasites develop in 
the same manner as the first generation and sometimes reach the stage of 
segmentation. In fact we have in one instance observed the development 
of three successive generations in such a culture. More often, however, the 
parasites begin to die out after the first segmentation and especially after 
the second. We have not been able to determine exactly the cause of this. 
In order to perpetuate the culture it is necessary to transfer a portion of 
the cells and parasites to a recently prepared tube containing fresh cells 
and serum. It is convenient to place the fresh serum in the culture tube 
and to take up in a large capillary pipette a portion of the cells and para- 
sites of the culture and then about five times the amount of fresh cells. 
These are mixed in the pipette with air excluded and then carefully spread 
on the surface of the plasma, paper shelf, or bottom of the tube, according 
to the particular kind of culture tube used. The transplantation should be 
done within four or five hours of the time of maximum segmentation and 
therefore approximately every forty-eight hours for tertian and estivo-au- 
tumnal parasites. 

The work of Bass and Johns has been confirmed by Lavinder in 
America; and Ross, Thomson and others in England. These dif- 
ferent workers have successfully cultivated the parasites accord- 
ing to the technic given and it will now be possible to study 
various questions related to malaria and malarial plasmodia in the 
test tube. 

FACTORS DETERMINING THE AMOUNT OF MALARIA IN 
A GIVEN COMMUNITY. 

From what has been gathered from the foregoing pages con- 
cerning the etiology of this disease it becomes apparent that the 
amount of malaria in a given community depends on three factors : 
the number of Anophelines present; the number of infected individ- 
uals from whom the mosquitoes are able to contract the infection; 
and the opportunities accorded the mosquito to bite man, resulting 
in the twofold process of their contracting the infection, and trans- 
mitting it. Ross in an elaborate system has worked out conclu- 
sions, largely by considering the laws of chance, on the likelihood 
of a given number of healthy persons, having among them a given 



ETIOLOGY OTHER FACTORS. 77 

number of infected individuals, contracting the infection, with a 
given number of Anophelines also present. He has elaborated on 
the necessary factors as follows : 

(1) That a person whose blood contains a sufficient number of 
gametids (sexual forms) is living in or near the locality. 

(2) That an anopheline capable of carrying the parasites sucks 
enough of that person's blood. 

(3) That this anopheline lives for a Aveek or more afterward un- 
der suitable conditions — long enough to allow the parasites to mature 
in it. 

(4) That it next succeeds in biting another person who is not 
immune against the disease or is not protected by quinin. 

The author wishes to draw attention to and to especially 
emphasize the fact that the significance of the number of gamete 
carriers has been almost lost sight of in considering the number 
of Anophelines. One is equally as significant as the other: a large 
number of Anophelines with a small number of malaria-infected in- 
dividuals holds the same relation toward the endemicity of the 
disease as a large number of gamete carriers with a small number 
of Anophelines. Eoss presupposes that the likelihood of mosquitoes 
succeeding in reaching man as being one chance in four, so that 
with a single Anopheline present and one infected person, in say a 
population of one thousand, the chance of this single mosquito be- 
coming infected by biting the single infected person, if it succeeds 
in reaching man at all, is one in four thousand. In continuing his 
deductions, this author shows that the next factor that has to be 
considered is the probable life of the mosquito. It must live a w T eek 
or longer to be capable of transmitting the infection, and he places 
the chance of the mosquito 's doing this as one in four, this reducing 
the likelihood of the insect 's maturing the infection to one in twelve 
thousand. Now, it has to bite another person, and the chance is, 
of course, the same as prevailed for the first biting, namely, one in 
four, making the total chance of an Anopheline succeeding in con- 
tracting and transmitting the infection as one in forty-eight thou- 
sand, in a community of 1,000 people containing one gamete carrier 
and one Anopheline ; but such a condition could of course never ex- 
ist in fact, as mosquitoes wherever present are in large numbers. It 
does not require much knowledge in mathematics to figure out, with 
the above illustration as a working basis, the likelihood of a given 
number of mosquitoes, with the presence of a given number of 



78 MALARIA. 

individuals carrying the sexual forms, being able to inoculate a 
given number of non-infected persons, and it emphasizes the fact 
that the presence of malaria, in either endemic or epidemic form, 
is necessarily governed as much by one factor as the other. There 
are many communities where the eradication of the mosquito is an 
almost hopeless task, and impractical, owing to the immense funds 
that would be necessary not only to eradicate them for a single 
season but to keep them continually eradicated, but it is within 
the power of any physician to eradicate the sexual forms of the 
parasite in man. Too much work, therefore, cannot be done toward 
the education of the public, not only on the role played by the 
mosquito, which is now generally accepted, but on the equally 
significant role played by man, which is understood very little if 
any by the average layman, and largely neglected by the physician 
in the treatment of his cases of malaria. This will be discussed at 
length in the chapter on the prophylaxis of the disease, and the 
significance of latent malarial infections as a predisposing etiological 
factor will be covered in a chapter devoted to latent malaria. 



CHAPTER V. 

PATHOLOGY— COMPLICATIONS— SEQUELJE 
—PROGNOSIS. 

PATHOLOGY. 

The pathology of malaria is especially characterized by changes 
in the blood, the other important changes, which are more or less 
pronounced, depending on the type and severity of the infection, 
being seen in the spleen, liver, kidneys, brain, bone marrow, and 
the intestinal tract. 

Entering largely into the pathological changes occurring in the 
malarial infections is the distribution of melanin and hemosiderin. 
The former is derived from the hemoglobin as a result of the action 
of the parasites on this blood constituent during intracorpuscular 
life. It is of a deep-brown or black color and is distributed within 
the blood, either free in the plasma, the plasmodia contained within 
the red cells, or the leucocytes, and also within the tissues. It is 
liberated at the time of sporulation of the parasites, is insoluble 
in acids, is free from iron, and freely soluble in sulphid of am- 
monium. Hemosiderin, on the other hand, is derived from the 
hemoglobin of broken-down red cells, other than those destroyed 
by the plasmodia. It is of a yellowish color, insoluble in acids, and 
contains iron. It is not found in the blood-stream, being deposited 
only in the tissues. 

Blood. — The very nature of the disease, the parasites attacking 
the red corpuscles, is such as to produce very great changes in the 
blood. The destruction of the corpuscles with the accompanying 
loss of hemoglobin rapidly produces an anemia, as a reduction in 
red corpuscles follows each paroxysm. Thayer states that "these 
reductions are more marked after the early paroxysms than after 
those occurring later. When a certain degree of anemia has been 
reached the losses per paroxysm are much less. When the number 
of corpuscles is reduced to 2,000,000 or 1,000,000, there is little 
tendency toward a further fall; sometimes there may be slight rises 

79 



80 MALARIA. 

in the curve between the paroxysms; often, however, the number 
of corpuscles remains stationary for weeks. In pernicious cases 
the number of corpuscles may fall between paroxysms." 

The rapidity with which this reduction is accomplished is very 
marked. Craig has observed a loss of 2,000,000 red cells per cubic 
millimeter within thirty-six hours in a case of tertian estivo- 
autumnal infection, and cites the cases of Turck with a loss of 
1,000,000 in one day, Mannaberg's with 1,000,000 in two days, and 
Kelsch's with 2,000,000 in two days, all of them being with the 
estivo-autumnal infections; and Grawitz records a case showing a 
loss of 4,000,000 red cells in six days. The author recently saw a 
case of tertian estivo-autumnal in a child two years old, where the 
red cell count was reduced to 2,000,000 per cubic millimeter in six 
days. The destruction of red cells is accompanied by a marked 
reduction of hemoglobin, which in severe cases may amount to 40 
per cent in a few days. This loss is not entirely due to the 
hemoglobin destroyed in those red cells attacked by the parasites; 
there is also a loss in those cells that do not become infected with 
parasites, apparently due to some toxic agent, of wmich fact ''there 
is additional evidence in the polychromatophilia and granular de- 
generation of the body of the red cell so often present in severe 
malarial infections." (Delaiield and Pruddem) 

The changes in the size, color, and form that occur in the ery- 
throcytes have already been discussed in the description covering 
the various species of the plasmodia. 

Leucocytes. — There is in nearly every malarial infection, except 
pernicious cases, whether of recent or old origin, a leucopenia, the 
leucocytes being reduced to 3,500, or even to 2,000, per cubic mil- 
limeter. This reduction may be preceded early in the infection by 
a leucocytosis which is present only for a short time ; in pernicious 
cases, however, leucocytosis may prevail, a count of 20,000 to 30,000 
per cubic millimeter being commonly observed. The white cells 
are frequently pigmented with granules of melanin. A differential 
count will often prove of great value in arriving at a diagnosis, as 
the lymphocytes will always be found very much in excess, the large 
mononuclears being especially numerous. The polynuclears and 
eosinophiles are reduced, especially the latter ; a malarial infection 
presenting evidence of eosinophilia is suggestive of an accompanying 
intestinal helminthiasis, a common coincident infection in countries 
where both diseases prevail. 



PATHOLOGY — COMPLICATIONS — SEQUELS — PROGNOSIS. 



81 



In 204 cases Krauss found the following differential count to 

be the average : 

per cent 

Small lymphocytes 14.8 

Large lymphocytes 19.5 

Polymorphonuclears 63.7 

Eosinophils 2.0 

Craig gives the average differential count in the various types 

of the infection as follows : 

per cent 

Polynuclears 52.ol Qmmt [u 

Small mononuclears 16.3 , , • 

y tertian 

Large mononuclears and transitionals 32.4 -, 

& malaria. 

Eosinophiles 3 



Polynuclears 52.0 

Small mononuclears 20.6 

Large mononuclears and transitionals 22.2 

Eosinophiles 3.0 



Count in 
quartan 
malaria. 



Polynuclears 45.0 

Small mononuclears 18.4 

Large mononuclears 5.0 

and transitionals 35.6 

Eosinophiles 1.0 



Count in 

estiyo- 
autumnal 
infections. 



Note the low count of eosinophiles in the benign tertian infections, 
the increase of 50 per cent above normal of these cells in the quartan 
infections, and the equal decrease from normal in the estivo- 
autumnal infections. The polynuclear count is relatively the same 
in all types of the infection, being slightly lower in the estivo- 
autumnal types. The difference in the small mononuclears is not 
marked, but the changes occurring in the large mononuclear count 
are especially so. Very high in the benign tertian, they are not 
quite so numerous in the quartan, reaching more nearly normal in 
the estivo-autumnal, while in the latter the count of transitionals 
reaches an exceedingly high mark. 

Spleen. — This organ is nearly always more or less enlarged. In 
the tertian infection it is especially so, particularly following re- 
peated attacks, but in estivo-autumnal infections this enlargement 
is not so marked, there often being but slight splenomegalia. except- 
ing in old long-standing cases. 



82 MALARIA. 

This enlargement in rare instances becomes so pronounced as to 
cause spontaneous rupture of the organ. Rupture may also follow 
puncture of the gland for diagnostic purposes, and on this account 
the procedure is not devoid of danger. Thayer speaks of a case in 
which this accident occurred following aspiration for diagnostic 
purposes, similar cases being reported by others. The spleen is of 
a dark-slate color or sometimes even black, caused by the pigment 
derived from the parasites and degenerated red cells. The pulp 
often becomes soft, sometimes assuming a diffluent character; it 
contains many red cells with the older forms of the parasites within 
them; the younger forms may also be present but are not so nu- 
merous as the older ones. The pulp sinuses contain free pigment, 
both melanin and hemosiderin being observed, the former a dark- 
brown or black color, the latter a golden-yellow. Areas of necrosis 
may be present. On section it appears a slate color, which in old 
infections is sometimes deepened, becoming almost black. The cap- 
sule becomes very much thickened as the infection persists, and is 
adherent to the surrounding tissues. The Malpighian bodies, not 
well marked early in an infection, become so in long-standing or 
repeated ones, or in improperly treated cases. The trabecular are 
markedly hypertrophied and usually contain pigment, the connect- 
ive tissue being increased. The venous sinuses become congested, 
and contain numerous plasmodia, both intracorpuscular and extra- 
corpuscular, pigmented leucocytes, and macrophages, phagocyto- 
sis being actively carried on by the latter. It has generally been 
held that in the estivo-autumnal infections crescents are especially 
numerous in this organ. Craig, however, states that he has never 
found them in any great numbers, and that they are often absent 
when they can be readily demonstrated in the peripheral blood. 
He reports two fatal cases of the disease in which long and patient 
searches were required to demonstrate the parasites in smears taken 
from this organ, and cites the case of Bloombergh and Coffin in 
which no plasmodia could be found in sections of the spleen but 
were demonstrated in the peripheral blood. 

Liver. — This organ usually becomes enlarged and is very much 
congested, presenting a dark-brown or black color, due to the deposit 
of melanin and hemosiderin. The consistence of the organ is gener- 
ally diminished, and the liver cells become swollen, contain hemo- 
siderin, and in old-standing cases hypertrophy, or may be supplanted 
by connective tissue. The endothelial lining of the capillaries are 



PATHOLOGY COMPLICATIONS SEQUELJE PROGNOSIS. 83 

studded with pigment, while the capillaries themselves contain 
numerous plasmodia and macrophages, the latter reaching very 
large sizes. Areas of focal necrosis may be present following in- 
tense infections with the estivo-autumnal types of the disease. On 
section the cut surface of the organ oozes blood, the congestion being 
very great. The gall-bladder is distended with dark-brown or black 
bile. 

Kidneys. — The changes taking place in the kidneys are not very 
marked except in severe cases. In these, it is believed that the 
changes that do occur are the result of some toxic substance in 
the blood rather than to the direct action exercised by the plasmodia 
within the organs. In repeated or severe infections the kidneys 
appear as slightly enlarged, and more or less congested, depending 
on the severity of the case. The capsule is not adherent. The 
Malpighian corpuscles are congested and contain hemosiderin, the 
epithelium of the convoluted tubules undergoes degeneration, and 
the straight tubules contain epithelial, hyaline, and granular casts. 
The glomeruli and intertubular capillaries may contain melanin, 
small numbers of parasites, leucocytes, and macrophages. In per- 
nicious cases the pathology of the kidneys may be that of an acute 
parenchymatous nephritis. 

Brain. — Except in pernicious malarial infections, the brain pre- 
sents few pathological changes. In severe cases, especially those 
that take on cerebral symptoms, the meninges are infected, conges- 
tion being marked; there will often be seen areas of punctiform 
hemorrhages, and the capillaries may contain immense numbers 
of plasmodia in different stages of development, in addition to pig- 
mented leucocytes, macrophages, and endothelial cells. The en- 
dothelium of the capillaries may be studded with both parasites and 
free pigment and may undergo fatty degeneration, while the cortex 
of the brain may appear almost black from pigment deposit. 

Bone Marrow. — This will vary in color from a pinkish to a deep 
brown or black, depending on the length of time the infection has 
been present and its intensity.' It contains numerous pigmented 
parasites, and the sexual forms of the estivo-autumnal infections 
are especially numerous. The marrow substance sometimes becomes 
diffluent and contains a large amount of pigment, and numerous 
macrophages. The capillaries may contain a larger number of 
Plasmodia, much free pigment, and many pigmented macrophages. 

Intestinal Tract. — The pathological changes occurring in the in- 



84 MALARIA. 

testinal tract are not marked except in exceptional instances. Cases 
presenting choleriform symptoms are more apt to be followed by 
pathological changes, consisting of highly congested blood-vessels 
containing numerous plasmodia within the red cells. Their en- 
dothelial lining may be severely pigmented and may undergo de- 
generative changes, sometimes resulting in thrombosis, necrosis, 
and hemorrhage. 

COMPLICATIONS. 

Pneumonia. — Pneumonia is a very common complication of ma- 
laria and is so often present that, previous to the discovery of the 
Plasmodia, it was considered as a manifestation of malarial infection. 
Both lobar and bronchopneumonia may occur, but the former is the 
more usual type present as a complication. It is more often seen 
in the estivo-autumnal infections and adds very much to the gravity 
of the prognosis, the mortality in such complicated cases reaching 
50 to 75 per cent. The pneumonic symptoms will usually overcome 
those of the original infection, although in some instances the clinical 
picture of pneumonia is much altered as a result of sporulating 
Plasmodia. 

An acute bronchitis is also a common pulmonary complication. 

Dysentery. — Dysentery, both specific and amebic, are very com- 
mon complications. In the United States Army General Hospital 
at San Francisco 65 per cent of soldiers suffering with malarial in- 
fections, and who had recently returned from service in the Philip- 
pine Islands, were found, by Craig, to be also suffering from dysen- 
tery. In 25 per cent of these cases he demonstrated the Entamoeba 
histolytica. All cases developing dysentery should undergo a care- 
ful examination to determine its origin, as it is common to see such 
attacks in latent malarial carriers, and if such examination of the 
feces proves negative, it is evidence of the fact that the dysentery 
is due to the malarial infection. In such cases the dysenteric symp- 
toms will rapidly subside under appropriate malarial treatment, and 
to the exclusion of any other line of treatment. The author has seen 
many cases of intestinal disturbance, varying from a mild diarrhea 
to a severe dysentery, that failed to respond to any pf the usual 
treatments for such conditions, but that rapidly recovered under 
quinin. 

Typhoid Fever. — While it is unusual to see malarial organisms 
remain in an active state throughout the course of a typhoid in- 



PATHOLOGY — COMPLICATIONS — SEQUELS — PROGNOSIS. 85 

f ection, they are frequently present during the first few days of the 
invasion, and their presence will often for a time render a positive 
diagnosis impossible. Craig has reported a case of coincident quar- 
tan infection which persisted throughout the course of a typhoid 
illness, and two cases of combined typhoid and estivo-autumnal 
malaria. Such infections are however rarely seen together, and 
while in malarial districts typhoid fever patients will often harbor 
the plasmodia in an active state during the first few days of the 
disease, their activity will be overcome early in the course of the 
infection. They will often reappear during convalescence from ty- 
phoid but are seldom seen all through its clinical course, but in 
spite of this fact, it is not unusual in certain sections of this country 
to hear the crude diagnosis of ' ' typho-malarial fever." This term, 
never worthy of a place in the vocabulary of an educated physician, 
should forever be relegated to the rear. It would be just as absurd 
to refer to a condition as ' ' diphther-malarial, ' ' where malarial para- 
sites were found in the blood of a child ill with diphtheria, as to 
apply the term typho-malaria to those cases showing malarial par- 
asites in a beginning typhoid attack. Care should always be taken 
to give the proper significance to the presence of malarial organisms 
in the blood, not forgetting that they may be but concomitant with 
some other pathological condition. 

Tuberculosis. — It is often impossible to differentiate between an 
incipient tubercular lesion and chronic malaria from the clinical 
picture alone. It was formerly held that the two diseases could not 
coexist, but this has proved to be an error. In fact, the loss of 
resistance, as a result of repeated malarial attacks, or from the 
chronic forms of the disease, renders such individuals particularly 
prone to all tubercular infections. The negro of the Southern 
states is peculiarly susceptible to tuberculosis, and the auft&r has 
seen many cases that were apparently induced by neglected riflflaria. 

Pregnancy. — It is a very common occurrence to see women during 
the lying-in period develop active malarial manifestations, where the 
disease has been in a latent state, possibly for many months or 
longer. It is a complication of the puerperal state that may give 
the attending physician considerable anxiety, and an examination 
of the blood for plasmodia should be conducted before deciding on 
treatment. 

Abortion. — Abortion and premature labor are common and serious 
complications of malaria. The percentage of pregnant women that 



86 MALARIA. 

will abort following malarial infection will depend largely on the 
type of infection that prevails, the complication being greater where 
the estivo-autumnal are the prevailing infections than where the 
tertian or quartan predominate. The author does not think that 
25 per cent is too high a figure to place on this complication, where 
the estivo-autumnal infections are present, but the outcome neces- 
sarily largely depends on treatment, which will be discussed later. 

Nephritis. — Nephritis is also a very common complication. It 
may occur during the acute stages of an infection, but is more often 
seen among the old sufferers of the disease. The frequency of the 
complication is given by various authorities in widely varying 
figures. Thus, Moore states that it is 80 per cent, and Thayer, that 
in the benign tertian and quartan infections it is 38.6 per cent, and 
in the estivo-autumnal types 58.3 per cent. Craig confirms these 
figures on the tertian and quartan, but has found, in his observations, 
that in the estivo-autumnal infections nephritis is present in 65 per 
cent of them. On the other hand, Deaderick and Ford both place' 
the complication as of rarer occurrence, 2 per cent or less being their 
figures, and there is no doubt that it varies a great deal under vary- 
ing conditions. Where the original infections are promptly treated, 
or where the infections are less intense, this and all other compli- 
cations will necessarily be fewer than when the disease progresses 
for a time with little or no treatment, or in those districts where 
intense infections prevail. 

Heart Diseases. — Valvular lesions of the heart may complicate 
malaria, rendering the prognosis a very grave one. A tachycardia, 
entirely out of proportion to the height of the fever, may be present, 
and during convalescence, bradycardia may be present for days, the 
pulse often being as low as thirty-five or forty. 

Hookworm Disease. — Of especial significance in the Southern 
states is the coexistence of uncinariasis and malaria. The author has 
seen many instances, where children suffering from hookworm dis- 
ease failed to improve following proper treatment, in spite of the 
fact that their feces became negative, and that blood-constructive 
tonics were administered. In many such instances he demon- 
strated the presence of malarial plasmodia, which had not been 
looked for in the enthusiasm of curing the other infection, and fol- 
lowing the administration of quinin they rapidly improved. The 
pathology of the two diseases renders an individual infected with 
one very susceptible to the other, and there is no doubt that many 



PATHOLOGY COMPLICATIONS SEQUEI;^ — PROGNOSIS. 87 

cases of hookworm disease result fatally, on account of a compli- 
cating malaria, too often overlooked. It is also equally true that, in 
many cases of malaria, a coexisting hookworm infection is over- 
looked, and the author would impress the necessity of a careful 
examination of both blood and feces of patients in whom we suspect 
either infection. 

The chronic nature of the disease when it is not properly treated, 
which unfortunately is the rule and not the exception, renders com- 
plications with almost any disease very likely, and we shall not 
discuss them separately. All of the infectious diseases, gonnorhea 
and syphilis, in fact all of the ailments the human race is subject to, 
may be and often are coincident with malarial infection. 

SEQUELAE. 

The sequelas of malaria are those that would naturally be looked 
for in such pathological conditions as are produced by the disease. 

In the Blood. — Anemia is a constant sequela to repeated infection, 
and while it does not often remain long following original attacks, 
where the blood-producing organs are not altered, it is necessarily 
persistent in those having recurring or repeated infections. The 
changes occurring in the blood have already been discussed in con- 
sidering pathology, and will not be dwelt on further here. 

In the Genitourinary System. — Nephritis is a common aftermath 
of repeated malarial infections. To malaria, more than to any other 
disease, can be attributed the high mortality rate from this affection, 
so common in all tropical and subtropical countries. It will but 
seldom occur after but a few attacks of malaria, but in repeated 
cases or in those that are not treated a sufficient time to entirely 
eradicate the infection, and in whom it remains latent, it is of very 
great frequency. 

In the Glandular System. — Splenomegalia is a constant sequela 
to chronic malaria, and is present more or less following each 
acute attack. It will not persist, except after repeated attacks, 
or in those improperly treated ; in such cases, however, the spleen 
may attain enormous size. Craig reports having seen two cases of 
spontaneous rupture of this organ, Banta reports a case, and Palmer 
records one in which rupture occurred within seven days of the 
initial symptoms of the disease. Other cases have been reported. 

The liver becomes enlarged following repeated infections and 
remains in a hypertrophied state, but in most cases the functions of 



OO MALARIA. 

the organ do not seem to be retarded. The author has seen two 
cases of cholecystitis which seem to have undoubtedly been brought 
on by malaria; in each instance the gall-bladder was drained, and 
the patient made an uninterrupted recovery. 

These are the most common sequelae of repeated malarial attacks. 
It should be borne in mind that the debility produced by this in- 
fection, when it is allowed to persist, is marked, and that these un- 
fortunates become easy prey for almost any other disease, and that 
in this manner malaria acts as a contributory cause to the general 
morbidity and mortality rates in districts where the disease prevails. 
It has been frequently shown that, following an active campaign 
against this disease, the accompanjdng decline in morbidity and 
mortality rates is not confined to malaria, but that a very general 
improvement in the health of the inhabitants follows upon the wake 
of such campaigns, which is well illustrated in the following table 
given by Ross : 

TABLE X. 

1. Cases of Malaria admitted to Klang Hospital from the Two Towns compared with 
those admitted from the District. 

Years 1901 1902 1903 1904 1905 

Towns 610 199 69 32 23 

Districts 197 204 150 266 353 

2. Deaths in Klang and Port Swettenham. 

Years 1900 1901 1902 1903 1904 1905 

Fever 259 368 59 46 48 46 

Other diseases .... 215 214 85 69 74 68 

3. Deaths registered in District, excluding Towns. 

Years 1900 1901 1902 1903 1904 1905 

Fever 173 266 227 230 286 351 

Other diseases 133 150 176 198 204 271 

(In the above tabulation the Towns referred to are Klang and Port Swettenham, in 
which active measures against malaria were commenced in 1902, the Districts referred 
to being the immediate surrounding territory, in which no measures were taken.) 

PROGNOSIS. 

It may generally be stated that the prognosis of the benign tertian 
and quartan types of malaria is always favorable, provided treat- 
ment is instituted, and even in those cases that are not properly 
treated, fatalities are rare, excepting in young children and infants. 
It should be borne in mind, however, that fatalities may occur in 
even a benign tertian infection when complications accompany the 
disease. The quartan infections, especially persistent, may act as a 
chief contributory cause of death if not properly treated. In all 
those cases, however, in which quinin is administered, even if not 
continued a sufficient time to entirely eradicate the infection, re- 
covery is the rule. However, even the benign tertian infections are 



PATHOLOGY COMPLICATIONS SEQUELS PROGNOSIS. 89 

responsible for many deaths among young children and infants, 
where a diagnosis is not arrived at until the infection has persisted 
for some days. The blood-producing organs, in these young children 
and infants, have not the power of accommodation that they have in 
adults, so that, in addition to overwhelming these little ones 
with toxins generated by the parasites, their tissues suffer from want 
of oxygen as a result of the destruction of the red corpuscles; and 
the author has seen many deaths from uncomplicated tertian infec- 
tions in children under one year, where the infection had been 
active for some days before treatment was instituted. On the 
other hand, infants and young children tolerate quinin better in 
proportion than do adults. 

In certain cases, while the asexual forms of the plasmodia may 
be in such small numbers as to produce clinical symptoms for but a 
short time, gametes may form in large numbers, and we have already 
adduced evidence that the intensity of an infection, on which the 
prognosis necessarily depends, is influenced entirely by the presence 
of heavy gamete carriers. Craig, in discussing prognosis, calls at- 
tention to a fact that has often impressed the Avriter. A study of 
mortality statistics, as compiled by the Bureau of the Census of the 
United States, will show that many cities of this country have ap- 
parently a very high death rate from malaria, when as a matter of 
fact, the disease is not at all general in some of them. Those famil- 
iar with conditions in the Southern states, while recognizing that the 
disease prevails in rural communities, and to a certain extent also in 
the centers of population, to a point that is not a matter for national 
pride, are perfectly well aware that the apparent high mortality 
rates given the Southern city as being due to malaria are not in ac- 
cord with the facts. Thus the statistics issued by this bureau give 
the following cities a death rate from malaria per 100,000 population 
as in the following table : 

TABLE XI. 

Key Wilming- Charles- 
Year. Savannah. West. ton. ton. Memphis. Norfolk. 

1904 104.5 35.3 205.1 46.3 138.8 17.7 

1905 154.5 19.5 116.6 42.7 122.1 22.4 

1906 100.6 28.3 130.1 35.5 118.4 28.4 

1907 111.6 22.9 74.0 24.8 100.9 26.3 

1908 122.3 13.3 64.5 44.3 96.5 20.0 

That such statistics are grossly incorrect is self-evident. For 
instance, the malarial death rate given Savannah, in 1908, is 122.3, 
which means that in a city of 71,000 (the estimated population of 



90 



MALARIA. 



Savannah for that year was 71,163) there occurred some 86 deaths 
from malaria, which, admitting a mortality of 1 per cent in the total 
number of cases, means that there were some 8,600 cases of malaria 
during the year. These errors are doubtless due to incorrect diag- 
noses, and Craig, in commenting on this situation, writes: "Noth- 
ing could illustrate more forcibly the immense importance of a 
scientific diagnosis of malarial fevers by an examination of the 
blood than does this quotation, and the condition of ignorance of 
the true nature of malaria which it portrays is a reproach to 
American medicine." 

The prognosis in estivo-autumnal fevers is good in treated cases, 
but when oft-recurring, or improperly treated, pernicious symptoms 
may develop with little or no warning, when the prognosis becomes 
extremely grave. 

It should be borne in mind that, while the prognosis in any given 
number of cases is favorable, there is probably no other disease 
that is so often a contributing factor to other illnesses, resulting 
fatally, as malaria, and that vital statistics from any source do not 
ever fully record the extent to which it is a contributory cause of 
existing mortality rates wherever the disease prevails. 

The following table given by Deaderick shows the mortality in 
various parts of the world, as recorded by various observers : 



TABLE XII. 



Author. 


Locality. 


Cases. 


Deaths. 


Laveran 


Turko-Russian War 


140,000 

1,310 

4,856 

1,954 

960,048 

7,352 

605 

1,373,355 

3,397 

2,308,128 

22,618 

281 

63 

301 

12,617 

17,468 

449 

1,784 

98,774 

1,055 

116,879 

6,618 

1,294 

5,003 

22,792 


1,092 






13 






22 






5,916 
984 




Hong Kong 

Camp Wikoff 

Civil War 




39 




15,423 
348 






Terburgh 


Dutch Indies . . 


114,490 
15 


Koch 






Koch 


East Africa 


2 


Hag-en 

British Colonial Reports 

Wright 


Papua . . 


23 
618 


British Malaya 

Baberton 

North Bengal 


680 




14 








7,432 
5 






Erni 


Dutch Indies 


731 




20 


Various Hospital Reports. . . . 
German Protectorate Reports. 
Malaria Society 


Southern States 

German Protectorates 

Italy 


30 

32 

120 








5,109,001 


148,055 



CHAPTER VI. 

DIAGNOSIS. 

Manson writes : ' ' There is a marked tendency to regard and diag- 
nose all fevers occurring in tropical countries, or in individuals who 
have returned from tropical countries, as malarial. Such slovenli- 
ness- in diagnosis must be strenuously avoided by the practitioner. 
It is apt to become a habit which, sooner or later, is bound to have 
disastrous consequences. ' ' 

It is doubtful if there is any disease so often incorrectly diagnosed 
as malaria. The error is made in both directions, many cases pre- 
senting irregular types of fever being classed as malaria, when some 
other pathological condition is responsible for the symptoms; and 
on the other hand, many cases of malaria remain unrecognized, 
in which the disease takes on irregular forms, owing to compli- 
cations, the presence of more than one group of parasites, or other 
conditions, such as improper treatment. In cases presenting typical 
symptoms even the most ignorant tyro can hardly fail to recognize 
the disease, but there are many cases in which all methods at our 
command are. necessary to establish a diagnosis. 

In a great majority of cases in which quinin has not been taken 
before an examination of the blood is made, such an examination 
will at once clear up the diagnosis, but the mere presence of Plas- 
modia in the blood should not stop the clinician from looking for 
other possible existing pathological conditions, nor should a single 
negative examination satisfy one that malaria is not present. In 
those cases in which there are more than one group of parasites, 
often nothing but a microscopical examination of the blood will 
suffice to establish a correct diagnosis. 

There are two methods by which a diagnosis of malaria is arrived 
at: clinical, and microscopical. Most writers in the past have in- 
cluded, in addition to these methods, the. quinin test, a therapeutic 
test method, in which a fever responding to quinin is classed as 
malarial, and one giving a negative reaction to the drug, as not of 
malarial origin. The author considers it a most pernicious habit 

91 



92 MALARIA. 

to rely on this therapeutic test in the diagnosis of suspected malaria, 
and the reason for taking such a stand is obvious. When a person 
presents himself for treatment it is important that a correct diag- 
nosis be established, so that treatment can be instituted, which will 
not only remove clinical manifestations, but insure the absolute 
elimination of the infection, thus making it impossible for him to 
later infect other mosquitoes. There are many fevers, other than 
malaria, that will respond to the action of quinin, and many more 
that are self-limited, so that in cases where a disappearance of 
symptoms may follow the administration of quinin, the fallacy of 
calling them malaria is apparent. 

Again, most writers have justified a diagnosis of malaria, from 
the clinical picture. "While in some instances circumstances may 
be such that we have to rely on the clinical picture alone, 
the time has come when nothing but a microscopical diagnosis 
should satisfy the practitioner, whenever it is possible to secure 
one. The oft-repeated statement, that the busy practitioner has 
not time to examine the blood of his fever patients, is ridiculous, 
and unworthy of anyone engaged in the practice of medicine. 
It would be just as absurd to make a statement that one has not 
time to make an urinalysis; for a blood examination for the detec- 
tion of plasmodia can usually be completed within a very few 
minutes in a great majority of cases, and is simplified by the appli- 
cation of the thick-film process for the detection of parasites, while, 
in those few cases that possibly do require more time than the gen- 
eral practitioner can give, a proper examination can be secured 
without any expense, at least in most of the Southern states, and 
in a great majority of other sections where malaria is prevalent, 
from the State Boards of Health, or other health authorities. A 
physician who has a small income may think that he cannot afford 
a microscope for such work, but the reverse is the truth; he can- 
not afford to be without one, and while it is not desired to com- 
mercialize this discussion, he will find that he can actually put his 
microscope to work in helping him earn a livelihood. 

The possibilities for error in the clinical diagnosis of malaria are 
so great, and the effect of failing to make a correct diagnosis so far 
reaching, that the author believes with Craig, who writes: "I 
believe that the time will come when it will be considered malprac- 
tice to neglect the blood examination in fever cases, and that he 
who loses a patient from malaria and has not recognized the disease 



DIAGNOSIS. 93 

because of the neglect of a blood examination will be amenable to 
the law." 

CLINICAL DIAGNOSIS. 

The clinical division that is generally followed, and to which the 
author will adhere, is that of tertian malaria, depending on the 
sporulation of the Plasmodium vivax; quartan malaria, depending 
on the sporulation of the Plasmodium malaria}; tertian estivo-au- 
tumnal malaria, depending on the sporulation of the Plasmodium 
falciparum; and quotidian estivo-autumnal malaria, depending 
on the sporulation of the Plasmodium falciparum quotidianum. 
Each of the clinical pictures, resulting from the benign tertian 
and estivo-autumnal tertian, show particular characteristics, de- 
pending on the type, and need in nowise be confusing, although the 
sporulation of both these parasites occurs every forty-eight hours. 

It is generally thought that the estivo-autumnal infections are 
characterized by fever of a remittent type; this is, however, in- 
correct, and it may generally be stated that all malarial infections 
are accompanied by an intermittent fever, when uninfluenced by 
complicating conditions. Craig in commenting on this point 
writes: "The impression that prevails among many physicians, 
that a remittent temperature curve is characteristic of all estivo- 
autumnal infections, is a false one, for irregularity or remittance 
is by no means confined to the estivo-autumnal infections, which, if 
uncomplicated, are as truly intermittent as are either the benign 
tertian or quartan fevers." 

In tertian malaria the Plasmodium vivax, sporulating every forty- 
eight hours, gives a very typical clinical picture, except in compli- 
cated cases, in those having more than one group of the parasites, 
or in cases having received small doses of quinin. This drug will 
often cause the picture to vary to such an extent that a diagnosis 
from clinical symptoms is almost impossible. 

The chill occurring every forty-eight hours, followed by a tem- 
perature ranging from 103° to 106° F., depending on the intensity 
of the infection, and the susceptibility of the patient, is sufficient to 
warrant a clinical diagnosis of tertian malaria. The periodicity of 
the chill, which will usually occur at the same hour of the day as 
the preceding one, the rapid rise of temperature, with the stage 
of decline following in a few hours, accompanied by profuse sweat- 
ing, is a picture that cannot be mistaken. 



94 MALARIA. 

In quartan malaria the parasite takes seventy-two hours to com- 
plete its cycle within man, so that what has been said of the clinical 
diagnosis of tertian malaria is even more marked in this type of 
the infection. The exacerbation of clinical symptoms occurring 
every fourth day makes the clinical diagnosis of quartan malaria 
an easy matter in single uncomplicated infections. On the other 
hand, periodicity is very irregular in quartan malaria except in 
single infections, so that the clinical diagnosis of this type is not 
satisfactory except under the most typical conditions. 

In no type of malaria is a clinical diagnosis more unsatisfactory 
than in the estivo-autumnal infections. The chill, accompanying the 
sporulation of the tertian and quartan plasmodia, is often absent 
entirely in the estivo-autumnal types, and even when present is 
usually nothing more than a chilly sensation, which may accom- 
pany or precede fever produced from almost any infection. The 
author has found that in the great majority of tertian estivo-au- 
tumnal infections there is no initial chill but that the temperature 
curve is very characteristic. While the temperature will come down 
to normal between paroxysms, it only remains there for a short 
time before the succeeding sporulation causes it to rise again. It 
is of course absolutely impossible to diagnose either of the estivo- 
autumnal infections from the clinical symptoms when complicated 
by a benign tertian or a quartan infection. 

In the quotidian estivo-autumnal infections the chill is more 
pronounced than in the estivo-autumnal tertian, occurring every 
twenty-four hours, followed by an elevation of temperature, and is 
sufficient upon which to base a clinical diagnosis in localities where 
it is known to be present. 

From the foregoing, it will be seen that periodicity, on which 
the clinical diagnosis of all types of malaria is dependent, may be 
interfered with by the previous administration of quinin, the pres- 
ence of double, multiple, or mixed infections, and by complications. 

The bete noir of the physician, in trying to arrive at a diagnosis 
of malaria, is the use of quinin in some form by the patient before 
presenting himself for examination. What would in many, in fact 
in nearly all, instances be an easy task is often made a compara- 
tively hard one by the use of this drug, taken in insufficient dosage 
to give much relief to the sufferer, but sufficient to very materially 
change the clinical picture of the disease. In a simple benign 
tertian infection, instead of a chill occurring with typical regu- 



DIAGNOSIS. 95 

larity every forty- eight hours, and followed by fever and sweating, 
there may be nothing but a history of an initial chill, with irregu- 
lar forms of fever, occurring at irregular intervals. The fact of 
having taken quinin will often be denied, but careful questioning 
will elicit the fact that some of the various so-called "chill and 
fever tonics" have been taken. These preparations, none of them 
having enough quinin to eradicate the infection, in many times 
the dose instructed to be taken, do, however, contain enough of 
the drug to materially alter the clinical picture. 

In double, multiple, or mixed infections it is evident that the 
presence of more than one group of parasites w T ill cause variations 
in the clinical picture. Thus a double tertian, instead of having a 
paroxysm every forty-eight hours, will have an exacerbation of 
clinical symptoms every twenty-four hours. A double quartan 
presents a very irregular clinical picture, depending on the time 
of sporulation of each set of parasites, whereas in a single infection 
of this type, the clinical course is a very distinct one. It is not 
necessary to describe in detail all of the other various irregular 
clinical pictures that the disease may assume under such condi- 
tions; for such variations depend entirely on the time of sporula- 
tion of the different groups of parasites, and it is an easy matter for 
the reader to figure out what each particular combination will 
result in clinically. 

Double infections of the benign tertian type are of common oc- 
currence, as also are mixed infections of the benign tertian and 
estivo-autumnal types, but the quartan, which is comparatively a 
rare infection, is not so often seen with a coexisting malaria of 
other types. 

The various complications that may occur in conjunction with 
malaria have already been discussed, and that these complications 
will result in variations of the clinical picture, depending on the 
particular symptoms of the complication, will be easily understood 
and will not be discussed at length. 

It is plainly evident that a clinical diagnosis of malaria is far 
from satisfactory except under the most typical conditions, and 
when it is taken into consideration that in a very large majority 
of cases an absolutely positive diagnosis can be secured in a few 
moments of time devoted to the examination of the blood of these 
patients, it is certainly very poor practice to depend on anything 
else or to fail to make such an examination. 



96 MALARIA. 

LABORATORY DIAGNOSIS. 

For the purpose of examining blood for the detection of malarial 
Plasmodia, it is useless to try to work with a lower power than a 
3-12 oil -immersion lens; this should be combined with an 8X eye- 
piece. The microscope should be provided with a diaphragm and 
condenser, and while a mechanical stage is not absolutely necessary, 
it very greatly facilitates the examination of a slide. It is im- 
portant that the student thoroughly familiarize himself with the 
picture of normal blood before relying on his examination of sus- 
pected malarial blood. 

The examination of unstained blood for diagnostic purposes is 
not to be recommended ; the small ring forms of the estivo-au- 
tumnal types are especially hard to detect in the unstained prep- 
aration, while the staining of a slide, after which it can be examined 
at any time, takes but a few moments, and greatly facilitates the 
detection of plasmodia. It is well, however, that the student work 
with unstained blood for the purpose of studying the morphological 
changes occurring in the various plasmodia. 

In preparing a specimen of fresh blood for examination, a small 
drop should be placed on a thin cover-glass, everted, and immedi- 
ately placed on a slide. Care must be taken that the drop be not 
too large, as it should be small enough to allow the corpuscles to 
spread out in a single layer, and not so large as to allow the forma- 
tion of clumps or rouleaux, for such a preparation is worthless. 
The treatment of fresh blood for the purpose of demonstrating the 
flagellate bodies has already been described, and a detailed de- 
scription of the morphology of the different parasites has been 
given in considering the classification of the parasites; it is there- 
fore not necessary to describe them here. 

While in the great majority of cases with active clinical mani- 
festations, a few minutes examination will suffice to demonstrate 
the plasmodia, a smear should not be pronounced negative, unless 
examined for at least twenty minutes, and the time of examination, 
that will be most likely to demonstrate the plasmodia, is a matter 
that should receive careful consideration. The most likely time 
for a physician to be called to see a case of malaria is during, or 
soon after, the chill. At such times an examination of the blood 
for the detection of plasmodia is apt to be a long and tedious one, 
while a smear taken some hours later would demonstrate them in 



DIAGNOSIS. 9 ( 

a very much shorter time. Thayer considers that the best time to 
look for the parasites is eight hours before or after the chill. The 
author has found that any time six or seven hours after an ex- 
acerbation, and up to within four or five hours of the succeeding 
paroxysm, will usually demonstrate them, whereas immediately fol- 
lowing, and for a few hours preceding a paroxysm, they are dif- 
ficult to find ; the schizonts can frequently be seen numerous in the 
peripheral circulation and gradually assuming advanced stages of 
development, only to disappear, suddenly, a few hours before 
sporulation. 

There are many objects in both the stained and unstained prep- 
arations that may to the untrained eye be mistaken for plasmodia. 
In unstained preparations, particles of dirt, that remain on the 
slide, may under an improper focus apparently be surrounded with 
what appears to be a protoplasm, and be mistaken for small ring 
forms. Small granules from broken-down leucocytes resting on a 
blood corpuscle are often mistaken for plasmodia, but they, of 
course, possess no ameboid action, which is sufficient to differentiate 
them from the parasite. Small vacuoles within the red corpuscle 
are very deceiving, but with a proper focus the greater refraction 
of the vacuole will serve to distinguish it from plasmodia, its 
edges being well defined, while the edges of the parasite taper off* 
as it were into the body of the red cell. Various causes may re- 
sult in retraction of the hemoglobin leaving areas devoid of this 
blood constituent, resulting in a picture which may also be mis- 
taken for plasmodia. Lack of ameboid movement with increased 
refraction should suffice to differentiate them. 

In the stained preparation, blood platelets are the most common 
objects mistaken for plasmodia. Their smaller size, the absence of 
pigment, with the chromatin granules, if present at all, very much 
finer than in the plasmodia, together with the absence of a blue- 
stained protoplasm, are the points that serve to differentiate them. 
Blood-dust is also very often mistaken for the young hyaline forms. 
From the above summary of some of the objects most frequently 
mistaken for malarial plasmodia, it will be seen that there are many 
pitfalls for the inexperienced observer, and there is little doubt 
that many get discouraged with their early attempts to establish 
malarial diagnosis by laboratory methods. Deaderiek in discussing 
this point writes: "Most students gain the impression that all 
that is necessary to find the parasites is to locale a malarial subject 



98 MALARIA. 

with any form of the disease and obtain the necessary blood at any 
stage of parasitic development, to stain it properly, and to inspect 
it under a high-power lens. Usually this is what he has been 
taught by textbooks and by teachers, and when he fails to detect 
the characteristic organisms in undoubted cases of malaria he is 
disgusted. The results of such teaching throw discredit upon a 
discovery whose practical importance is unsurpassed in modern 
medicine." It should be remembered that very often the stained 
specimens that have been seen by medical students during laboratory 
courses in college have been chosen from exceptionally rich infec- 
tions, and that in actual practice cases in which blood is found con- 
taining such a profusion of parasites may be of comparative rare- 
occurrence. At the same time we are confident that anyone wishing 
to familiarize himself with the various species of parasites and with 
their different stages of development will have but little difficulty 
if they are persistent, and give attention to detail in the preparation 
of their smears. After a few cases have been diagnosed positively 
with the microscope, and the parasites recognized beyond any doubt, 
the satisfaction is such, that one soon becomes dissatisfied with any- 
thing but a laboratory diagnosis, if it is possible to make it. 

In addition to the presence of plasmodia in arriving at a labora- 
tory diagnosis, the presence of pigmented leucocytes are of con- 
siderable significance. This pigment (melanin) is also often seen 
free in the blood-plasma ; but the difficulty of differentiating it 
from particles of dust is such that it has little, if any, diagnostic 
value except when seen in the leucocytes. Craig writes, "when, 
however, the pigment is observed enclosed in mono- or polynuclear 
leucocytes; when it is of a characteristic golden-brown or blackish 
color ; and when several pigmented leucocytes are observed in two 
or more smears, carefully prepared, we are justified in making a 
diagnosis of malarial infection, either past or present." This last 
statement is one that should not be passed lightly. Just as the mere 
presence of malarial plasmodia may not mean malarial infection 
to the exclusion of all other pathological conditions, the presence of 
pigmented leucocytes may simply be evidence of a malarial infec- 
tion "past or present," and may not necessarily be a factor in the 
existing illness. It is therefore not safe to depend too strongly on 
the presence of pigmented leucocytes, in establishing a diagnosis 
of malaria, without ascertaining beyond all reasonable doubt that 
some coexisting pathological condition is not also present. 



DIAGNOSIS. 



99 



With the stained slide, in looking for plasmodia, it is well at the 
same time to count and record the leucocytes, securing a differential 
count, the significance of which has been dwelt on in considering the 
pathology of the disease. A total leucocyte count for the purpose 
of determining whether or. not a leueopenia is present will serve 
as an auxiliary in making a laboratory diagnosis, and still another 
link in the chain may be secured by using the color index to deter- 
mine the percentage of hemoglobin. 

To summarize, in arriving at a malarial diagnosis by laboratory 
methods, we are assisted by: (1) the detection of plasmodia, (2) 




Fig. 22. — Preparation of blood smear, the size of blood drop, and angle at which slide 

is held. 



pigmented leucocytes, (3) a differential leucocyte count, (4) an 
absolute count, and (5) determining the percentage of hemoglobin. 
In the preparation of a blood-smear we may choose from two 
methods: one, the thin film, in which the blood is spread out in 
a thin even smear, allowing the examination of each individual 
erythrocyte; the other, the thick-film method, in which a thick 
smear is made, in which, the hemoglobin being removed, the leu- 
cocytes, stromata of the red corpuscles, and the contained para- 
site, if present, are left for examination. The latter method has 
the advantage of allowing the examination of a much larger quan- 
tity of blood in a much shorter time than is permitted in the use 
of the thin film, but it also has its disadvantages, which will be 
dwelt on in the description of the method. 



100 



MALARIA. 



The Thin-Film Method. — A number of slides having been 
cleansed (and for this purpose there is nothing more satisfactory 
than washing them well with soap and water), the lobe of an ear, 
or a finger, is cleansed, dried, and punctured with a coarse needle. 
After rejecting a drop or so of blood, a small drop is placed on 
the slide by just touching it to the blood, not permitting the skin 
to come into contact with the glass. The specimen slide is now held 
between the thumb and finger of the left hand and at an angle of 
about forty-five degrees (Fig. 22), and the end of another slide 
(contact slide) held in the right hand is brought into contact with 
the blood drop, which will then be seen to flow by capillary attrac- 




Fig. 



23. — The contact slide, the blood running to the edges of the specimen slide by 
capillary attraction. 



tion to the outer edges of the specimen slide (Fig. 23). The con- 
tact slide is now moved with a very light movement upward along 
the surface of the specimen slide, which will result in a thin even 
smear (Fig. 24), provided the slide is clean and free from oily 
substance. Scrupulous care in the cleansing of specimen slides 
and not allowing the skin to come in contact with the glass will 
avoid much trouble by eliminating particles of dust and debris from 
collecting on the specimen. While the beginner will possibly make* 
many errors in the detection of the young hyaline ring forms, espe- 
cially of the estivo-autumnal types, he will soon overcome this 
trouble, and with a little practice will soon learn to reject those 
small particles of blood-dust and debris, that, until properly focused 






DIAGNOSIS. 



101 



on, resemble or at feast are often mistaken for the young malarial 
ring form. In fact, the picture of even the youngest hyaline ring 
form of an estivo-autumnal infection cannot be mistaken for any- 
thing else after familiarity with their staining qualities and mor- 
phological structure is acquired, which is done with a little practice. 
While films may be stained after they are many days old, the film 
of more than a few hours does not take the stain as well as the 
fresher preparation. 

There are many methods of staining the malarial plasmodia. 
The author has used with universal success Wright's mod- 
ification of the Leishman stain, which he has found a most 




Fig. 24. — The contact slide having been passed rapidly upward over specimen slide, a 
thin even smear resulting'. 



satisfactory one for all blood work, while the malarial parasites are 
perfectly stained by properly observing the technic, which is more- 
over a most simple one, requiring but little practice to become per- 
fectly familiar with. Certain objections to the use of this stain, as 
prepared under the original technic. have recently been overcome 
by a revised modification in the preparation of the staining fluid, 
which is given by Wright as follows : 

To a 0.5 per cent aqueous solution of sodium bicarbonate add methylene 
blue (B.X. or "medicinally pure'*) in the proportion of 1 gram of the dye 
to each 100 cubic centimeters of the solution. Heat the mixture in a steam- 
sterilizer at 100° C. for one full hour, counting the time after the sterilizer 
has become thoroughly heated. The mixture is to be contained in a flask, or 



102 MALARIA. 

flasks, of such size and shape that it forms a layer not more than fi centi- 
meters deep. After heating, allow the mixture to cool, placing the flask in 
cold water if desired, and then filter it to remove the precipitate which has 
been formed in it. It should, when cold, have a deep purple-red color, when 
viewed in a thin layer by transmitted yellowish artificial light. It does not 
show this color while warm. To each 100 cubic centimeters of the filtered 
mixture add 500 cubic centimeters of 0.1 per cent aqueous solution of "yel- 
lowish, water soluble" eosin, and mix thoroughly. Collect the abundant pre- 
cipitate which immediately appears on a filter. When the precipitate is 
dry, dissolve it in methylic alcohol (Merck's reagent) in the proportion of 
0.1 gram to 60 cubic centimeters of the alcohol. In order to facilitate solu- 
tion, the precipitate is to be rubbed up with the alcohol in a porcelain dish, 
or mortar, with a spatula or pestle. This alcoholic solution of the precipitate 
is the staining fluid. It should be kept in a well-stoppered bottle because of 
the volatility of the alcohol. If it becomes too concentrated by evaporation 
and thus stains too deeply, or forms a precipitate on the blood-smear, the 
addition of a suitable quantity of methylic alcohol will quickly correct such 
faults. It does not undergo any spontaneous change other than that of con- 
centration by evaporation, according to my personal experience. A most im- 
portant fault encountered in the working of samples of this fluid is that it 
fails to stain the red corpuscles a yellow or orange color, but stains them 
a blue color which cannot be readily removed by washing with water. This 
fault I have recently discovered to be due to a peculiarity of the eosin em- 
ployed. It can be eliminated by using a proper "yellowish, water soluble" 
eosin. Such an eosin I have obtained from R. L. Emerson, 739 Boylston St., 
Boston. 

It requires not a. little practice to properly prepare this stain, 
and if improperly done the resulting fluid is worthless. Those who 
have not the facilities or who do not wish to give the time necessary 
to acquire the technic can obtain the stain already prepared under 
the name of "Wright's Blood Stain" from any reputable physi- 
cian's supply house. 

The technic for the use of this stain is as follows : 

Cover the slide with thirty or forty drops of the staining fluid or enough 
to thoroughly cover the preparation. At the end of a minute add the same 
amount of distilled water, allowing the solution to remain another two min- 
utes or slightly longer if an intense coloring is desired. Now wash the slide 
in distilled water, for from a few seconds to a minute or so; this is an im- 
portant step, and requires some practice to perfect. If the washing is con- 
tinued too long, the blue staining of the protoplasm of the parasites, if present, 
becomes washed out. rendering their detection difficult. On the other hand, 
if the washing is not sufficient, the corpuscles will remain a bluish color, also 
.rendering the detection of the parasites more difficult than when a proper 
differential staining is obtained. The time to cease the washing is when the 
film is just turning a pinkish or reddish-yellow color. If it is desired to pre- 



DIAGNOSIS. 103 

serve the slide, it should not be mounted in an acid balsam, which results 
in the decolonization of the parasites in a short while. During the staining 
process it is well to place the slide on two parallel glass rods, which 
will have the effect of preventing all the fluid running off, if an excess hap- 
pens to be placed on the slide; whereas, if it is allowed to rest on a flat 
surface, and the fluid once starts to run over the edge, most of it will drain 
off. After the slide is sufficiently washed, it is our custom to rapidly take 
up the remaining water on the slide with a smooth surface blotting paper, 
for the purpose of preventing a further de color ization. After examination, 
the slide, if to be preserved, should be carefully wiped off and placed in a 
suitable case that will insure its being kept free from dust accumulations. 

Among other methods used for the staining of the plasmodia may 
be mentioned the Komanowsky, the Leishman, and the Nocht. 

In the Romanowsky method two stock solutions are required. One consists 
of methylene blue (Griibler). 1 part, sodium carbonate, 1.5 part, distilled 
water, 100 parts; the other of a 1:1000 aqueous solution of "yellowish, water 
soluble'' eosin. 

For staining, 5 cubic centimeters of each solution are added to 95 cubic 
centimeters of distilled water; these two solutions are then mixed, using one 
part of the methylene-blue solution to two parts of the eosin solution. This 
stain is then applied to the film and allowed to remain for fifteen or twenty 
minutes, or longer, and then thoroughly washed in distilled water. This 
method is not so satisfactory as the Wright modification, the staining reactions 
being the same, but the technic requiring a much longer time. 

The Leishman method calls for the preparation of the following staining 
solution : 

Methylene blue 1 part 

Sodium carbonate 0.5 part 

Distilled water 100 parts 

This solution is heated for twelve hours at 05° C, and then kept in room 
temperature for several days. At the end of this period a 1:1000 solution of 
"yellowish, water soluble" eosin is added to it, in equal parts, mixed, and 
allowed to stand for six to twelve hours. The precipitate which forms is 
then collected on a filter paper, washed with distilled water and dried, and 
.013 gram of the dried filtrate is dissolved in 100 cubic centimeters of methyl 
alcohol (Merck's reagent). The application of this staining fluid is similar 
in technic to Wright's stain, the smear being covered with the fluid for two 
minutes, distilled water added in about double the proportion of the stain 
used, the dilution being allowed to remain for about five minutes, when the 
film is washed in distilled water. 

Ewing gives the following description of the Nocht method : 

(1) To 1 ounce of polychrome methylene blue (Griibler) add 5 drops of 3 
per cent solution of acetic acid (U.S. P.. 33 per cent). 

1 1 ) Make a saturated (1 per cent) watery solution of methylene blue, 
preferably Ehrlich's rect. (Griibler), or Koch's, dissolving the dye by gentle 



104 MALARIA. 

heat. This solution improves with age, and should be at least one week old. 

(3) Make a 1 per cent solution in water of Grtibler's aqueous eosin. 

The mixture is prepared as follows: 

To 10 cubic centimeters of water add 4 drops of the eosin solution, 6 drops 
of neutralized polychrome bind, and 2 drops of 1 per cent methylene blue, 
mixing well. The specimens, fixed in alcohol or by heat, are immersed for two 
hours, specimen side down, and will not overstain in 24 hours. The density 
of the blue stain may be varied to suit individual preferences. The above 
proportions need not be rigidly followed, but the polychrome solution should 
be accurately neutralized. 

The Thick Film-Method. — Ross, in 1902, described a method 
for the detection of parasites in the blood by which one is en- 
abled to examine a thick film of blood, instead of the method previ- 
ously used in which a thin film is fixed and stained. His method 
consists of taking a large drop of blood scarcely spread out at all, 
and when dry, removing the hemoglobin by gently washing with 
water, and then staining the residual film. This results in the 
worker 's being able to examine a very much larger amount of blood 
in a very much shorter period. The method does not seem to have 
come into general use in this country, and for which the author 
is unable to see the reason ; for in many instances the advantages 
are so great that, once the technic is acquired, it will always be 
used in certain types of cases, where the parasites are few and dif- 
ficult to find in the thin-film method. The relation of the parasite 
to the red corpuscle is of course destroyed, and one has to be fa- 
miliar with the picture of the parasites to work with the method to 
advantage ; but once the technic is mastered the saving of time is 
so great that one is well repaid for the time devoted in becoming 
familiar with the method. It is of especial value where there is 
reason to believe that, in spite of the absence of clinical symptoms, 
the infection has not been eradicated. In cases that have marked 
clinical symptoms and in which there has been no quinin adminis- 
tered in any form, there will usually be no difficulty in making a 
laboratory diagnosis with the thin film, but in those cases that have 
taken quinin, in some of the so-called "chill tonics," or in other 
forms, in doses insufficient to control the clinical manifestations, 
but sufficient to cause the majority of parasites in the peripheral 
blood to seek the deeper tissues, the thick film is especially valua- 
ble. Owing to the thickness of the residual film, after the hemo- 
globin is removed, the parasites appear in various irregular shapes, 
to an even more marked degree than in the other method. 



DIAGNOSIS. 105 

The technic, originally suggested by Ross, has since been ampli- 
fied and modified by Ruge, Bell, and Laing, and by James and the 
author in this country. 

Ross' original technic is as follows: 

A quantity of blood, say 1 cubic millimeter, is spread over only about t4 
square centimeter of area, and allowed to dry. Tbe hemoglobin is then 
washed out with water, and the residue, consisting of parasites, leucids, 
micrids, and the stromata of the hematids, is stained by any appropriate 
method. 

James was the first in this country to publish the results of work 
carried on under a modified process of his own, and the author 
published, a few weeks later, another modification which he had been 
perfecting for some time previous. James' modification is as fol- 
lows : 

A thick smear having been made as previously described, the slide is im- 
mersed in ethyl alcohol, which has been acidified by the addition of ten drops 
of commercial hydrochloric acid to 50 cubic centimeters of the alcohol. The 
slide is left in this solution until the hemoglobin is removed, which takes from 
ten to twenty minutes, depending- on the thickness of the film. The slide is 
now washed in running tap water a sufficient time to remove all traces of the 
acid, this step taking from fifteen to twenty minutes. The smear is now 
ready for staining, which can be accomplished by any of the usual methods, 
taking well the Wright stain. It requires a little longer time to properly 
stain a thick film than is required in working with thin films, and the 
dilution must be greater when the water is added. 

An objection to this technic is the time involved, although, if it 
is not desired to make immediate examination of the film, it may 
be left in the acidified alcohol and the process completed at the 
convenience of the examiner. 

The following modification suggested by the author results in the 
saving of considerable time, and when the technic is carefully ob- 
served presents a pretty picture. It is as follows : 

A thick smear having been made and allowed to dry, the slide is gently 
immersed in a 5 per cent solution of glacial acetic acid for from one-half to 
two minutes, depending on the thickness of the smear, or long enough to 
remove the hemoglobin, then washed in 95 per cent ethyl alcohol for a few 
seconds, rinsed in distilled water, covered with a 2 per cent solution of 
sodium bicarbonate for twenty seconds, washed in water, then in alcohol, and 
without drying, stained. For this purpose we have used Wright's, but as in 
the James' or any thick-film technic, in adding the water, it is necessary that 
the dilution be greater than is used when working with a thin smear. The 
entire process including the staining is completed in a little over five minutes. 
Only such ingredients as are chemically pure should be used, including in all 



106 MALARIA. 

instances distilled water; and it is imperative that the acid should be neutral- 
ized, or the protoplasm of the parasites will not take the blue stain. It is 
also important that the alkali should not be in excess 1 , or the film will take 
an intense stain from the methylene blue, which cannot be satisfactorily 
washed' out without also decolorizing the parasites. Of course, in this method, 
as in all thick-film methods, the relation of the parasite to the corpuscle is 
lost, making the identification of the parasites more difficult to one not per- 
fectly familiar with the picture. It should be stated that the acid solution 
results in a shrinkage of the protoplasm of the parasites, while the crescents 
of the estivo-autumnal infections, as a result of this action, appear very much 
smaller, but their general contour is in nowise affected, so that there is 
absolutely no difficulty in their recognition. 

The importance of an examination of the blood in all malarial 
countries cannot be overestimated. There are so many other 
diseases having a more or less high rate of mortality, the clinical 
picture of which may resemble that of malaria, which may terminate 
in recovery if properly diagnosticated, but which, if treated for 
malaria, may run a very much longer and more serious course, or 
even terminate fatally, that it is of extreme importance that a 
diagnosis of malaria should not be made unless the infection is 
really present. On the other hand, it is of equal importance that 
all cases of malaria be classed and treated as such, not only for the 
period during which clinical symptoms are present, but also until 
all forms of the parasite are eradicated. On this account it is very 
necessary that, in every case where malaria is suspected, an ex- 
amination of the blood should be made, and not only a single ex- 
amination for the purpose of establishing a diagnosis ; for the duty 
of the attending physician has only commenced when such a diag- 
nosis is made, and he shirks one of the most important duties he 
owes to the community in which he lives, unless he keeps these 
patients under observation for several weeks, not discharging them 
until satisfied by repeated examinations of the blood that all forms 
of the plasmodia are eradicated. When malaria is treated in such 
a manner, then, and not until then, can we hope to see any great 
permanent reduction of the disease in those communities where it, 
while endemic, is not accompanied by a high mortality rate, or 
where the infections are not of great intensity. In districts where 
these latter conditions prevail, a combination of all the methods at 
our disposal for the prevention of the disease are apt to slowly be- 
come generally observed and followed out, and will gradually have 
to result in the reduction of the disease, but with the present at- 



DIAGNOSIS. 107 

titude of the majority of general practitioners, the outlook for the 
eradication of malaria is far from encouraging. In considering 
the prophylaxis of the disease, much has been written on the educa- 
tion of the laity ; to this propaganda should be added the education 
of the physician on the proper treatment of the disease, to a point 
where he will desist from the pernicious habit, which is a common 
one, of withdrawing treatment from a case of malaria just the mo- 
ment that there is no clinical evidence of the infection. 

DIFFERENTIAL DIAGNOSIS. 

Typhoid Fever. — There is no difficulty in differentiating this 
disease from the tertian or quartan infections, but with the estivo- 
autumnal types, it is often impossible to make a differential diag- 
nosis without the aid of the microscope. The use of the term 
typho-malaria has already been dwelt on. In 1898, during service 
with the Second Army Corps, in the Spanish-American War, the 
author saw hundreds of cases sent from his own and other regi- 
ments to the division hospitals, with diagnosis of malaria, and 
typho-malaria, practically all of which were afterward declared 
to be typhoid fever. Dock, who made an investigation of the preva- 
lence of malaria in this corps, writes, ' k In the first division hospital 
I was told that there were a great many cases of malaria and 
typho-malaria. Several so-called typical cases of the latter had 
no parasites and were evidently uncomplicated cases of typhoid 
fever." Fully 50 per cent of the cases of typhoid fever occurring 
in our troops during the Spanish-American War were incorrectly 
diagnosticated, and the physicians who made these errors were 
certainly of as high a standard of efficiency as prevails among gen- 
eral practitioners in civil life. Of these cases incorrectly diagnos- 
ticated 90 per cent were attributed to malarial infections, and when 
it is considered that with our present laboratory methods a positive 
diagnosis can be secured in fully 95 per cent of both these fevers, 
it is very evident that we should not endanger the lives of such 
patients, by relying on a clinical diagnosis. The presence of the 
Plasmodia and the absence of the Widal test will generally establish 
a malarial diagnosis. It must not be forgotten, however, that ma- 
larial plasmodia may be present during the first few days of a 
typhoid invasion, or during convalescence, and that the Widal re- 
action may not be secured until after the seventh day, and in some 
instances may not be present during any stage of the disease. Such 



108 MALARIA. 

eases should receive antimalarial treatment, being carefully watched • 
and if after four or five days of vigorous treatment the fever is not 
under control, typhoid fever should be suspected, and the treat- 
ment governed accordingly. In those cases negative to the Widal 
reaction, and resistant to quinin, the diagnosis of typhoid, if pres- 
ent, can be established by a blood-culture. A valuable auxiliary 
test for the purpose of establishing a diagnosis of typhoid in 
undetermined cases of fever is the macroscopical agglutination 
test of Bass, and a differential leucocyte count will also be of 
assistance in determining between malaria and typhoid fever, a 
marked rise of mononuclears, accompanied by a leucopenia, being 
characteristic of malarial infection. 

Dengue. — This disease may be confused with malaria unless a 
blood examination is made. Clinically, the prostration from dengue 
is more marked than in those forms of malaria with which it is 
likely to be confounded. Pain is a much more prominent symptom 
of dengue than of malaria and is more intense. The epidemicity 
of dengue will often be of help in determining a diagnosis, the 
rapidity with which the disease spreads, when once introduced, be- 
ing very marked. Whole families will rapidly become ill, and from 
50 to 75 per cent of the entire population may develop the disease in 
a remarkably short time. 

Abscess of the Liver. — This, a common pathological condition in 
tropical countries, is often confounded with malaria, but as in other 
conditions, an examination of the blood will clear up the diagnosis. 
It should be remembered, however, that the plasmodia often coexist 
with this pathological condition, and care must be taken in the 
significance attributed to their presence. As it is a common sequela 
to specific and amebic dysentery, these diseases, often complicated 
with malarial infection, make it imperative that, in suspected cases 
of abscess of the liver, too much importance be not given the mere 
presence of plasmodia. Pain and tenderness over the liver region, 
with enlargement of this organ, and absence of splenomegalia, dif- 
ferentiate the diseases clinically, but in old malarial subjects there 
may, however, also be an enlargement of the spleen. 

Cholecystitis. — The author has often seen this condition mistaken 
for malaria. There may be a periodicity in the chills, resembling a 
double tertian or a quotidian infection. An examination for the 
plasmodia, and a differential blood-count will clear up the diagnosis. 
In cholecystitis there will be a leucocytosis, with a large relative 



DIAGNOSIS. 109 

increase of the polynuclears, which is not the blood picture in a 
malarial infection. 

Appendicitis. — The author recently reported a case of benign ter- 
tian malaria with very marked symptoms of appendicitis. An ini- 
tial chill, followed by a temperature of 99.2° F., with intense pain 
over the region of the appendix, vomiting, and a marked rigidity of 
the right rectus, caused a tentative diagnosis of appendicular colic. 
The following day the condition had very much improved, and the 
patient was comparatively comfortable, but forty-eight hours from 
the initial symptoms, a chill, with all the previous accompanying 
symptoms intensified, and a temperature of 106° F., which fell in 
a few hours to nearly normal, caused him to suspect malaria, at least 
as a complication. An examination of the blood revealed the ter- 
tian plasmodia in large numbers ; antimalarial treatment was fol- 
lowed by a complete cessation of all abdominal symptoms, and the 
patient went on to a rapid recovery. Other similar cases have been 
reported. Appendicitis can be differentiated from malaria, by the 
absence of plasmodia in the blood, and a marked leucocytosis, with 
great excess of polynuclears. Too much attention should not be 
paid to pain in the belly, as it is often a prominent symptom in 
malaria, as well as in appendicitis. 

Yellow Fever. — Where this infection is suspected, especially im- 
portant is the examination of the blood for plasmodia, by which 
means only, in many mild cases, can a differential diagnosis be se- 
cured. While in severe cases of yellow fever distinctions are 
marked, in atypical cases there is a great similarity to the bilious 
remittent type of malaria. Albumin in the urine, present early in 
yellow fever, is not often seen in malaria until the infection has 
persisted for at least several days. The spleen is not enlarged in 
yellow fever, but in patients who have been more or less chronic 
sufferers with malaria, splenomegalia may be present. In yellow 
fever, a blood examination will show the absence of any increase of 
the large mononuclears, always present in a malarial infection. 

Tuberculosis. — This disease is often confounded with chronic ma- 
laria. The clinical picture that these unfortunates present is in 
many instances very similar in either infection. In pulmonary le- 
sions, the examination of the sputum will generally demonstrate the 
Bacillus tuberculosis; the blood picture is usually that of a lym- 
phocytosis, the lymphocytes being in great excess, the plasmodia 
being absent. Physical examination will disclose the physical signs 



110 MALARIA. 

present in a pulmonary tuberculosis, and as the disease advances, 
both these and the subjective symptoms render the diagnosis an 
easy matter. It is important, however, that a differential diagnosis 
be reached early in such infections, for many cases of tuberculosis, 
treated some months for a chronic malaria, and nothing else, may 
result fatally; whereas, if a diagnosis had been reached early in 
the disease, the prognosis might be affected. Contrary to former 
opinion, as has already been stated, the two' diseases may coexist. 

Kala Azar. — For a long time, and until recently, this disease was 
considered as nothing but a manifestation of malaria. It has now, 
however, been established as a disease per se, and the specific cause, 
the Leishman-Donovan bodies, has been isolated. The character- 
istic symptoms of this disease — an irregular fever, enlarged spleen, 
anemia, with more or less marked prostration — are such as to make 
almost impossible a differential diagnosis, where the two diseases are 
known to exist, without an examination of the blood. Quinin is 
said to have no effect on the clinical course of kala azar. 

Dysentery. — The common coexistence of this disease with malaria 
makes it very hard, in some instances, to definitely determine the 
significance of plasmodia when they are found in cases of fever hav- 
ing symptoms of a dysentery. Where the dysenteric symptoms are 
due to specific or amebic origin, an examination of the feces will 
suffice to establish the diagnosis, by the finding of B. dysentericce, 
or amebae. It is therefore imperative, in trying to arrive at the 
etiology of a dysentery, in countries where all of these infective 
agencies are present, that a careful microscopical examination be 
made, not only of the blood of these patients, but also of their feces. 

Sunstroke. — The known effect of exposure to the sun in tropical 
countries on latent infections, causing them to assume an active state, 
and the fact that in the estivo-autumnal types of malaria such 
activity may be accompanied by pernicious symptoms, often make 
it hard to differentiate between such an attack and sunstroke. An 
examination of the blood in such cases is generally sufficient to clear 
up any doubt. Craig speaks of three cases that he saw brought 
into hospitals, supposed to be suffering from sunstroke, which on 
examination of the blood showed numerous plasmodia, establishing 
a diagnosis of malaria. 

Septic Infections. — The similarity of the clinical pictures of ma- 
laria and puerperal sepsis has been already mentioned. Any septic 
or pyemic infection may simulate malaria. Thus pyelitis has often 



DIAGNOSIS. Ill 

been overlooked, and the disturbance attributed to malaria. Ulcera- 
tive endocarditis may also simulate the infection. A blood exam- 
ination in any of these instances is sufficient to establish a diagnosis. 
The presence or absence of plasmodia, a leucopenia with an increase 
in the large mononuclears indicate malaria; while a leucocytosis 
with increase of the polynuclears would suggest a septic condition. 

A very important matter, upon which the author has frequently 
touched, but which he wishes to emphasize, is the significance of 
Plasmodia in the blood, in so far as other pathological conditions are 
concerned. It matters not under what circumstances the plasmodia 
are found, their presence is positive evidence of malarial infection. 
It is very necessary, however, to determine if their presence is the 
sole cause, or is even a factor in an existing illness. The finding 
of plasmodia in the blood often results in there being no further 
search made for other existing disease, where, as a matter of fact, 
the plasmodia, while possibly being a factor in the clinical picture, 
are not alone responsible for the production of the symptoms for 
which the patient has sought relief. 

In regard to the relative frequency of the different infections, 
it may generally be stated that the benign tertian is as a rule the 
most frequently seen in both temperate and tropical countries. In 
certain sections of the tropics the estivo-autumnal types will be more 
often encountered, while the quartan is a comparatively rare in- 
fection in almost all localities. Of 2,803 cases of malaria observed 
by Craig, in soldiers returning from the Philippine Islands and from 
Cuba, 839 suffered from tertian malaria, 220 being double infec- 
tions. The relative infrequency of the quartan type is shown by the 
same writer, who states that in 5,000 cases in which the plasmodia, 
in some form, were demonstrated there occurred only 26 quartan 
infections. In something over five hundred cases observed by the 
author in Florida during the past three years, but two cases of 
quartan malaria were encountered, and in several hundred observed 
in the Philippine Islands during the years 1900-1901, but three or 
four cases of this type are recalled. Of the estivo-autumnal types, 
the tertian is more frequent than the quotidian. Of 1,662 estivo- 
autumnal infections personally observed by Craig in the Philippine 
Islands, 1,173 were tertians. The report of the Department of 
Sanitation of the Isthmian Canal Commission for the year 1911 
shows that there were 5,421 discharges and 25 deaths from estivo- 
autumnal infections ; 836 discharges and no deaths from benign ter- 



112 MALARIA. 

tian infections; and 72 discharges and no deaths from quartan in- 
fections. 

SYMPTOMATOLOGY. 

Tertian Malaria. — The symptoms of a single uncomplicated ter- 
tian infection are peculiarly characteristic. Exacerbations occur 
every forty-eight hours, at the time of the sporulation of the invad- 
ing organism, the Plasmodium vivax. The clinical symptoms of the 
disease may be divided into three distinct stages : ( 1 ) the stage of 
chill; (2) the stage of fever; and (3) the sweating stage, during 
which there is a decline of the fever and a comparative feeling of 
comfort comes over the patient. 

Stage of Chill. — The chill may for some days be preceded by a 
prodromal stage, in which loss of appetite, a general feeling of 
malaise, headache, and more or less aching of the bones are present. 
With its initiation the patient complains of coldness of the extremi- 
ties, followed by a feeling of chilliness running up and down the 
spine; this later involves the entire body, and the patient shivers 
with cold. The lips appear blue, the general appearance being one 
of cyanosis, and the patient goes into a rigor, sometimes so severe 
as to shake the bed. While the chill, which lasts from a few minutes 
to an hour, seldom longer, is still on, the temperature commences to 
go up, and in many cases reaches 104° F., or even higher; nausea 
is generally present, and vomiting may occur; the pupils are gen- 
erally dilated ; the pulse of small volume and very rapid. The 
foregoing is a description of a typical tertian rigor, but it should 
be remembered that many cases will be encountered in which sporu- 
lation is accompanied by less marked symptoms, the patient simply 
complaining of slight, creepy chilly sensations, with slight headache, 
and unaccompanied by excessive high temperature. 

In young children the initial symptom may be a convulsion. The 
author has known children playing around, apparently perfectly 
well, to be seized with convulsions, causing great alarm to the par- 
ents. 

Stage of Fever. — While fever is present during the chill, the pa- 
tient is unconscious of it, and the surface of the body appears cold. 
This is now rapidly succeeded by the hot stage, in which the patient 
experiences an alternate feeling, of discomfort from excessive heat, 
and a return of the chilly feeling. These sensations may alternate 
for an hour or more, when the chilliness entirely disappears, and the 



DIAGNOSIS. 113 

patient becomes extremely uncomfortable, complaining of intense 
fever. The pulse now becomes full, sometimes dicrotic, and remains 
very rapid. The face becomes congested, having an apoplectic ap- 
pearance, the conjunctivae are usually injected, the respirations are 
rapid, and a bronchial cough is very often present. The discomfort 
of the patient increases, and he feels very ill ; vertigo may be com- 
plained of, the headache is most severe, and pains in all parts of the 
body are complained of, being particularly severe in the back. The 
patient becomes very restless and at this time delirium is frequently 
present. The temperature may reach 105° F. or 106° F. Herpes 
is quite common, appearing on the lips or around the nose. This 
stage usually lasts four or five hours ; it may be prolonged beyond 
this time or occasionally be of shorter duration. 

Sweating Stage. — As the fever commences to subside, the patient 
breaks out into a perspiration, which is accompanied by a general 
relief from the disagreeable symptoms and discomforts of the pre- 
ceding stages. The perspiration is sometimes very profuse, the 
coverings and bed becoming drenched. The temperature now falls 
rapidly, and the patient becomes, as a rule, very comfortable. With 
the disappearance of the fever, the headache and other pains com- 
plained of subside ; the patient may fall into a sound sleep, and 
within three or four hours the temperature has usually become nor- 
mal. With the sweating stage over, the patient may feel perfectly 
well in a few hours, and the following day is often ready to assume 
general routine duties. There may, however, remain a feeling of 
lassitude, and a slight headache. 

The entire period from the initial chill to the abatement of symp- 
toms occupies as a rule from ten to twelve hours. As . before 
stated, it should be remembered that there may be very many varia- 
tions in the clinical picture, and the symptoms accompanying sporu- 
lation may be very slight, in some cases not sufficient to place the 
patient in bed; in fact, the intensity of the symptoms is governed 
by the intensity of the infections, and the resistance offered by the 
infected individual. Sporulation occurs every forty-eight hours 
from the time the sporozoite is injected by the mosquito, but clinical 
symptoms occur only when sporulation has resulted in the forma- 
tion of a sufficient number of merozoites to overcome the resistance 
of nature's forces. 

If treatment is not instituted, in about thirty-six hours from the 
subsidence of clinical symptoms, or forty-eight hours from the time 



114 MALARIA. 

the chill appears, another rigor takes place, followed by the same 
train of symptoms. Although sporulation usually occurs with reg- 
ularity, paroxysms sometimes occur a few hours before the expected 
time. In such cases the attack is referred to as an "anticipating 
one"; while in those cases in which sporulation of the plasmodia is 
prolonged, either by improper treatment, or by other conditions, the 
attack is said to be "retarded." Following the completion of a 
single cycle, the spleen, often very tender, is generally enlarged, 
and practically always is after two or more cycles are completed. 
After the infection has persisted for a few days, from 25 to 40 per 
cent of cases will show traces of albumin in the urine, but this, as a 
rule, does not persist much beyond the period in which clinical 
symptoms are manifest. 

Quartan Malaria. — The symptoms of a quartan infection, in a 
general way, simulate those of a benign tertian, except that, sporu- 
lation occurring only every 72 hours, exacerbations take place every 
fourth day. The prostration during the second stage may exceed 
even that seen in the benign tertian, and pernicious symptoms may 
intervene at any time. The period occupied by the entire three 
stages is of from eight to ten hours' duration. While a single un- 
complicated infection with this type of parasite gives a peculiarly 
typical picture, it should be borne in mind that double or triple 
infections necessarily alter the picture, and while the latter are 
comparatively rare, double infections are not at all uncommon. 
Physical examination of a patient suffering from a quartan infec- 
tion presents the same signs as those seen in a benign tertian. 

ESTIVO-AUTUMNAL INFECTIONS. 

Tertian Form. — While sporulation of this type of parasite in- 
volves the same length of time as does the parasite of the benign 
tertian, there are decided variations in the clinical pictures of the 
two infections. The prodromal symptoms are, as a rule, more 
marked than the benign form; loss of appetite, severe pains in the 
back and legs, with a dull heavy headache, accompanied by an ex- 
tremely restless, nervous condition, characterize the prodroma. The 
gastric disturbance is more pronounced, and vomiting is often very 
severe. There may be no distinct chill ; in fact, this is not, as a rule, 
very pronounced. The patient is likely to complain of a mere chil- 
liness; the headache and pains throughout the body, especially in 
the back, become more severe, there is often an expression of fear 



DIAGNOSIS. 115 

over the countenance, and the general nervousness of the patient is 
very pronounced. He has the feeling of impending disaster, the 
pulse becomes more frequent and is very weak. The patient feels 
much prostrated. Respirations become increased, and the tem- 
perature commences to go up, reaching 102° or 103° F. The high 
temperatures of the benign tertian are not so frequent in the estivo- 
autumnal types, except in those cases that take on pernicious symp- 
toms. The stage of chilliness lasts from ten minutes to half an 
hour, seldom longer. 

As the chilliness disappears the patient commences to feel the 
effect of the high temperature. He becomes very miserable, with 
a severe headache, pains in his back, and throughout his body, these 
symptoms often being accompanied by severe abdominal pain, sug- 
gesting the necessity of surgical intervention for appendicitis or 
cholecystitis, unless the diagnosis is established. The prostration 
at this period may be very intense, the pupils are usually dilated, 
and the face flushed. Polyuria is generally present, the urine often 
contains albumin, and microscopical examination will often show the 
presence of hyaline and granular casts. This stage is of much 
longer duration than the similar stage of the other malarial infec- 
tions, lasting from eighteen to twenty hours, sometimes even longer. 

The sweating stage is less pronounced than that in the benign ter- 
tian or quartan types, there never being the intense perspiration so 
often seen in the other infections. The skin is simply moist, and* a 
general mild perspiration may be noticed. The temperature, which 
had commenced to decline toward the end of the second stage, now 
becomes normal, and in many cases subnormal. This stage also lasts 
longer than does the similar stage of a benign tertian or a quartan 
infection, the three stages usually covering a period of from thirty 
to thirty-six hours. The maximum temperature during the fever 
period is usually 103° or 104° F., seldom higher. Its course is apt 
to be more or less irregular, and does not undergo the steady decline 
seen in the benign tertian form. The fact that there is often but 
a few hours between the subsidence of one paroxysm and the suc- 
ceeding one, has created the impression among a great many prac- 
titioners that the fever in a tertian estivo-autumnal infection is of 
a remittent character. In uncomplicated single infections, if care- 
fully noted, the temperature curve will show a decided intermission, 
while a double infection with this type of parasite is apt to produce 
a continued fever, with an oscillating curve. The above symptom- 



116 MALARIA. 

atology of an estivo-autumnal tertian does not include those cases 
which develop pernicious symptoms, which will be considered by 
themselves later. 

Quotidian Form. — This type, produced by infection with the 
Plasmodium falciparum quotidianum, presents clinical exacerbations 
every twenty-four hours, concomitant with the sporulation of the 
parasite. The chill is more distinct than in the type previously de- 
scribed, and there is often a decided rigor. It is not, however, quite 
so pronounced as in the benign tertian. The rise in temperature is 
marked, and rapidly reaches its maximum, which is usually in the 
neighborhood of 103° F. The drop, which commences usually within 
four or five hours from the initial symptoms, is pronounced, sweating 
is quite profuse, and the entire three stages usually occupy not more 
than ten hours. The other clinical symptoms of headache, pains in 
the back and extremities, and general prostration, are the same in 
both types of estivo-autumnal disease. 

PERNICIOUS FEVERS. 

Pernicious malaria is not a disease per se, but may occur in cases 
developing an intense intoxication. On account of the fact that it 
is commonly seen in the estivo-autumnal infections, it has been 
considered by some as forming a special classification associated with 
the estivo-autumnal types. This is incorrect, for, while nearly all 
cases of pernicious malaria are associated with estivo-autumnal in- 
fections, cases of any type of malaria may develop pernicious forms, 
rarely being seen in the benign tertian and seldom in the quartan. 
It is not uncommon to see a patient apparently doing well during 
an attack of estivo-autumnal fever, when, without warning, serious 
symptoms may develop. The author recalls a case in his private 
practice some months ago, in which a young girl, fourteen years of 
age, had been ill with an estivo-autumnal tertian infection for nearly 
a week. Previous to his being called, she had been indifferently 
treated, but the first time he saw her, there was nothing in her con- 
dition to cause any alarm. At 8 o 'clock in the morning her clinical 
picture was that of a moderate infection. She had a temperature 
of 101° F., and felt fairly comfortable, being in no great pain. At 
2 o 'clock the same afternoon, the author was hurriedly sent for, and 
on reaching the bedside found the child in tonic convulsions. She 
lapsed into coma in a short time, and in spite of all therapeutic 
measures, was dead in less than three hours. Many such cases are 



DIAGNOSIS. 117 

reported in the literature, and should serve to warn all practitioners 
living in sections where these types may be encountered to be ever 
alert and ready for danger signals. We will therefore consider 
pernicious fevers under the head of symptomatology, as the different 
types seen really are the symptom-pictures that may be observed in 
any case of malaria taking on pernicious symptoms. 

The author agrees with Thayer, who states that pernicious symp- 
toms rarely if ever appear with the initial paroxysm of original 
infections, and that they are the result of neglected treatment. This 
must not be interpreted to mean that pernicious symptoms may not 
be primary ones in recurring cases, for, as a matter of fact, they 
often are, but that such symptoms do not develop early in original 
infections. The responsibility of the treatment of original infections 
is here again emphasized. It is in those cases that receive treat- 
ment during the clinical course of the disease, only to have it with- 
drawn at the end of a few days or a week, ■ that are apt at any time 
to develop pernicious attacks, which would not occur if the treat- 
ment had been carried on a sufficient time to entirely eradicate the 
infection. The author has seen several cases of pernicious malaria 
in which young children, who appeared to be perfectly well, were 
stricken down while at play, and recalls two instances in which 
death occurred within twenty-four hours from the onset of the 
disease, in spite of the fact that treatment was instituted within a 
few hours of the initial symptoms. All of these cases gave histories 
of previous recent infections, and when it is taken into consideration 
that these young lives would not have been blotted out if their orig- 
inal illness with malaria had received appropriate treatment, the 
full significance of this carelessness is impressed upon us. 

Factors in the production of pernicious symptoms are exposure, 
alcoholism, intercurrent disease, or an}^ condition that results in the 
lowered resistance of the individual. It may generally be stated 
that pernicious symptoms develop as a result of an intense toxemia, 
generated by excessively large numbers of plasmodia, and governed 
by the individual susceptibility, natural resistance, or previous con- 
dition of the patient. The plasmodia may not appear in great pro- 
fusion in the peripheral circulation, in fact, may sometimes be hard 
to find at all, but smears secured by spleen puncture will show large 
numbers in different stages of development. 

The chief pernicious types of the disease are the comatose, eclamp- 
tic, algid, choleriform, pneumonic, and the bilious remittent. 



118 MALARIA. 

Comotose Type. — Coma does not generally occur in original infec- 
tions until after the patient has had several paroxysms, but when 
appearing in the course of a recurring infection, it may be a pri- 
mary symptom. It may develop gradually, or the patient may be 
stricken down suddenly as in apoplexy ; and in the latter form the 
most energetic measures are necessary to save the patient from death, 
which may occur within a few hours. In all cases developing symp- 
toms of coma, in malarial Countries, the blood should be examined 
at once for plasmodia, as a routine measure, a procedure which will 
save many cases that without a proper examination would be classi- 
fied as apoplexy or sunstroke. In apoplectic seizures the blood is 
often the only index of the disease. The temperature generally 
reaches about 103° F., seldom becomes higher, the face congested, 
respiration rapid, the pulse of high frequency, small volume, and 
irregular. In cases developing coma gradually, there are no espe- 
cial symptoms other than those seen in an ordinary attack; the 
patient is gradually overwhelmed with the toxin, and there may for 
a time be slight delirium, which gives way to a complete coma. The 
respirations may now become stertorous, the pulse becomes thready, 
weak, and very irregular, and the temperature may now become 
high, reaching 105° or 106° F. The patient may regain conscious- 
ness after a few hours, and go on to recovery, or may after a short 
while lapse back into unconsciousness, when death usually occurs 
from collapse. 

Eclamptic Type. — This is a common type in young children. 
They are seized with violent pain in the back of the head, vomiting, 
followed by eclamptic seizures, after which they lapse into a pro- 
found coma. The fever is usually high, 104° or 105° F., the pulse 
rapid and full, respirations hurried, and the skin hot and dry. If 
the case is not seen early and prompt treatment instituted, death, 
in the majority of instances, ensues within a few hours. 

Algid Type. — This type may be seen as a primary symptom in 
recurring or repeated infections, but more often follows after sev- 
eral paroxysms have occurred. It is characterized by, and pre- 
sents the picture of, a complete prostration that accompanies the 
invasion: the surface of the body is cold, a cold clammy perspira- 
tion is very profuse, and the patient appears in collapse. The face 
is drawn, the eyes sunken, the voice feeble, the radial pulse may 
be imperceptible, cyanosis is usually present, and the respirations 
are feeble and rapid. The temperature is, as a rule, not high, and 



DIAGNOSIS. 119 

in many instances will be subnormal. It is the most severe and 
dangerous of the pernicious types, and in spite of all treatment 
death may take place within a few hours from the initial symptoms. 

Choleriform Type. — In a certain number of malarial infections 
symptoms closely resembling those of Asiatic cholera may appear. 
The stools become very numerous, taking on the characteristic 
rice-water stool of cholera, and may be accompanied by blood. 
During the first few hours of the appearance of this complication 
the fever is usually high, but rapidly falls; the patient becomes 
extremely weak from loss of fluid, while suppression of urine may 
be complete. The skin becomes cold and clammy, and the patient 
appears cyanotic. Death takes place from collapse, where the 
infection is not recognized and properly treated, but when the 
case receives prompt attention, recovery is the rule. The diag- 
nosis of this type may be extremely difficult, and in sections where 
cholera is prevalent, an examination of the blood is the only method 
by which a positive diagnosis of malarial infection can be made. 

Pneumonic Type. — Pneumonia may be mistaken for this type of 
pernicious malaria, it being a very common complication. The 
pernicious type takes on symptoms of a lobar pneumonia. In it, 
the plasmodia become localized in the capillaries of the lungs, 
resulting in a symptom-complex, closely resembling that of a pneu- 
monic infection. Pain in the side, cough, and dyspnea are pres- 
ent. A moderately severe malarial infection may be running a 
typical course, when such symptoms develop and a pulmonary com- 
plication be suspected. "While the physical signs of a pneumonia 
may be present, the temperature curve is unlike that seen in pneu- 
monia, and with the subsidence of the malarial paroxysm, the 
pulmonary symptoms disappear spontaneously, possibly to return 
again with the next paroxysm. Careful observance of the clinical 
picture for twenty-four hours, or a little longer, together with an 
examination of the blood, will establish a diagnosis. 

Bilious Remittent Type. — A peculiar type of pernicious malaria 
is that when the patient is seized with uncontrollable vomiting, 
jaundice is present, the patient extremely prostrated, and the case 
may be mistaken for yellow fever. In vomiting, large quantities 
of bile are ejected, the fever runs a high course, and is usually of a 
remittent type; the patient may become delirious, or coma may 
supervene. In such cases nothing but a blood examination will 
reveal the true nature of the infection. When treated, practi- 



120 MALARIA. 

cally all of these cases will recover, but if neglected, death, may 
occur. 

Other Types. — There are many other pernicious types that may 
occur in malarial infections, such as the apoplectic, hemiplegic, 
typhoidal, tetanic, diaphoretic, cardialgic, aphasic, asthmatic, gas- 
tric, and rheumatic. They are comparatively rare, and will not be 
described separately. They take on the symptoms suggested by 
the applied terms, and as shown in the description of the various 
types of pernicious malaria just described, emphasize the fact that 
the only safe rule in all malarial countries is to make a routine 
practice of examining the blood of all cases in which there is 
any likelihood of the malarial plasmodia being a factor in the 
clinical symptoms, or in cases where it may be likely that the 
disease may be present in a latent or masked form. 



CHAPTER VII. 
LATENCY— RECURRENCES— CHRONICITY. 

LATENT MALARIA. 

The general subject of latent malarial infections as a predom- 
inating factor in the etiology of the disease is one that has been 
very generally overshadowed in the discussion of the other source 
of infection, the mosquito. Not only this, but the general view 
of the practitioner has been such in the treatment of the disease 
as to allow of the perpetuation of the infection in many places, 
where with proper treatment of such cases the disease would have 
rapidly disappeared. The author does not desire, that anything 
in the following pages should be interpreted as the taking of any 
stand against mosquito extermination to the point of greatest 
possible reduction. All that he wishes to impress upon his readers 
is that we have in the past very much neglected man as a focus 
of infection. In discussing climatic conditions, favorable to the 
life span of the malarial parasites, it has already been shown that 
in many sections of the world, following the winter months, the 
infection has been eradicated by nature, in so far as the mosquitoes 
are concerned, and that, before they are again capable of pro- 
ducing the infection in man, it is necessary for them to feed on 
the blood of infected man — that is, blood containing the sexual 
forms of the parasite. This means that, if in a given community 
all latent malarial infections were cured in these winter months, 
mosquitoes could breed promiscuously, bite us freely, but that 
we should remain free of malarial infection. If, in addition to 
this, all imported cases, and those few that escaped observation, 
were properly treated just as soon as they were discovered, ma- 
laria would soon become a disease of the past. 

It is a common occurrence to find plasmodia in the blood of 
patients suffering from other disease, and in that of those ap- 
parently well, and who appear to be suffering no inconvenience 
as a result of harboring the parasites. These are latent malaria 
carriers, and it is this class of cases that perpetuate the disease 

121 



122 MALARIA. 

in those sections where meteorological conditions are snch as to 
destroy the parasites in the mosquito during the winter months, 
and is a most serious factor in any community considering a cam- 
paign against this disease. Absolutely responsible for the per- 
petuation of the disease in temperate climates, where the mosquito 
becomes free of infection during the winter months, the latent 
carrier also largely enters into the dissemination of it in even 
tropical countries, and it cannot be emphasized too strongly that 
the destruction of the plasmodia in these carriers is equally as 
important as is the destruction of the mosquito. 

While such individuals may be apparently well, their hemo- 
globin index, and red corpuscle count, will always be below normal, 
and as a result of the pathological changes, brought about in acute 
attacks, which become more or less pronounced in the chronic car- 
riers of the infection, their resistance becomes very much lowered. 
This results in all malarial countries having a higher mortality 
rate, exclusive of that directly due to malarial disease, than coun- 
tries in which this disease is not present. The significance of 
malaria as a social factor is one that by a great many is not fully 
realized. Outside of the loss of labor resulting from malarial 
attacks, the actual earning power of individuals suffering from 
repeated attacks of malaria is very greatly decreased. 

The presence of latent malaria has therefore a multiple signifi- 
cance : namely, lowered resistance, rendering such individuals sus- 
ceptible to other disease; decreased earning power; and the 
provision of means for the perpetuation of the infection by the 
presence of sexual forms of the plasmodia, which will be taken up 
by the mosquito and undergo evolution whenever climatic condi- 
tions are favorable. 

There has been comparatively little work done showing the per- 
centage of latent carriers in malarial districts. Craig found 307 
latent cases out of a total of 1,297 soldiers invalided home from 
the Philippine Islands. The same author cites the history of 
Company H, 16th United States Infantry, in which, upon return- 
ing from service in the Cagayan Valley, located in the upper end 
of the Province of Luzon, he demonstrated the plasmodia in 27 of 
47 men doing duty, apparently well, and with no symptoms of 
malarial infection. Byrd has recently carried on some observa- 
tions in the state of Florida, to determine the malarial index of 



LATENCY RECURRENCES CHRONICITY. 



123 



that state. The following table comprises the results of his in- 
vestigations : 

TABLE XIII. 



White. 



Colored. 



Place. 

Sarasota 

Miami 

Little River .... 
Cocoanut Grove . 

Fort Pierce 

Oxford 

DeLand 

Arcadia 

Gainesville 

Dade County .... 

Total 



No. 


Pos. 


Neg. 


% 


No. 
16 


Pos. 


Neg. 


60 


2 


58 


3.5 


6 


10 


117 


6 


111 


5.1 











10 





10 


0.0 











10 





10 


0.0 











76 


2 


74 


2.6 


24 





24 


45 


3 


42 


6.6 











55 


5 


50 


9.1 


45 


5 


40 


31 





31 


0.0 











73 


8 


65 


10.9 











99 
576 


7 


92 
543 


4.9 



85 


1 




74 


33 


5.7 


11 



37.5 



0.0 
11.1 



12.9 



ETIOLOGY OF MALARIAL RECURRENCES. 

Probably the most important point that is so far undetermined 
concerning our knowledge of malaria is the etiology of recurrences ; 
in fact, it may be said that our knowledge of the disease and all 
that pertains to it is pretty complete with this single exception, and 
in reviewing the literature on this phase, one is impressed with the 
diametrically opposed views held by the various authorities, all of 
which are entitled to consideration. 

The theories advanced in the past have not been many, and in 
recent years have been limited to the following: 

(1) Parthenogenesis, or the reproduction of the organism by un- 
fertilized macrogametes. 

(2) Intracorpuscular conjugation, this being a process in which 
the young hyaline forms effect union with each other inside the 
corpuscle, resulting in a resting body, a resistant form capable of 
assuming a zygote stage, multiplying after periods of quiescence 
and only then giving clinical evidence of their presence. 

(3) Asexual reproduction by schizogon}^ this reproduction tak- 
ing place continually from the time of infection, and continuing 
after the subsidence of clinical symptoms, but then in numbers in- 
sufficient to produce clinical symptoms excepting under certain 
unknown conditions, when activity is resumed. 

Parthenogenesis. — In 1903, Schaudinn advanced the theory that 
the macrogametes took on a parthenogenetic cycle — that is, were 



124 MALARIA. 

able to multiply without fertilization by the microgametes — and 
attributed to this cycle recurring infections. Several other in- 
vestigators had previously described sporulating gametes, but had 
not attributed to the cycle the significance that this author did, 
and while the theory may appear to be a reasonable one, it has not 
been generally accepted. Deaderick has subscribed to it, but of- 
fers no evidence in its support except to cite the case of Frau 
Kossel, reported by Schaudinn, in which it is claimed an altera-' 
tion of the species was observed. Ross criticizes the deductions 
drawn from this case, calling attention to the fact that during the 
period that this patient was under observation the gametes varied 
in number, and that while there was a marked increase in their 
numbers the day before a paroxysm, considers that there was no 
evidence that they were not produced from ordinary spores, but 
that their variation in numbers itself suggests that they were 
being produced all the time, and that the source of asexual spores 
from which he considers that they were derived were too few to 
be detected by the method used. He calls attention to the fact 
that the cells were not actually observed in the process of de- 
velopment, but that it was inferred such development took place 
from a study of different cells in what was considered different 
stages of evolution. Deaderick, however, in following his line of 
argument in support of the theory, states that "these relapses at 
long intervals can be explained by parthenogenesis alone. After 
the schizonts have perished, ' while the microgametocytes do not 
persist long, the macrogametes remain for indefinite periods." In 
discussing a similar claim made by Schaudinn in the benign tertian 
infections, Craig does not confirm this statement in connection with 
estivo-autumnal infections, claiming that the male and female gam- 
etes remain in the blood for weeks after acute clinical evidence 
has passed away, and in practically the same ratio during the 
periods of observation. This has also been the author's experience 
in the estivo-autumnal infections seen in Florida. 

In an address before the Liverpool School of Tropical Medicine, 
Ross stated that many of their cases suffering from relapses never 
showed any of the sexual forms, thus indicating that they are not 
a factor in this form of the disease. He and Thomson, in a series 
of cases, record, in several of them, a marked rise in the curve of 
sexual parasites, unaccompanied by any rise of temperature. In 
one case the gametes reached the high number of 1,500 per cubic 



LATENCY RECURRENCES CHRONICITY. 125 

millimeter, remaining over a thousand for nine days, during which 
time there was no elevation of temperature, notwithstanding the 
fact that no antimalarial treatment was instituted. With these 
cases in mind, it is hard to associate recurring malarial infections 
with the theory of sporulating gametes. If such phenomenon re- 
sulted in recurrences, why is there no elevation of temperature in 
these cases showing a marked increase in the gametes and un- 
hampered by treatment of any kind? To gather the full signifi- 
cance of this objection to the theory, we must recall the etiology 
of. fever in malaria, which, as has already been stated, is due to 
the liberation of toxins at the time of sporulation, so that it is 
reasonable to infer that, if the sporulation of gametes, if such does 
occur, were a factor in recurrences, an increase of their numbers 
to any extent would be accompanied by an elevation of temperature. 
While it may be hard to reject what such an authority as Schaudinn 
reports as a positive finding, we cannot ignore the significant state- 
ment made by Thomson, that the phenomenon has never been ob- 
served by workers in the Liverpool School of Tropical Medicine, 
and "must be very rare, as it would otherwise have been noticed 
more often." If it is necessary to adduce further evidence that 
the sexual forms are not a factor in recurrent infections, it would 
seem that the question could be absolutely settled by inoculation 
experiments with blood containing only those forms. Ross cites 
four such experiments, one conducted by Thayer in 1898, and 
three by Elting in 1899. All of these were negative, three of them 
showing neither fever nor parasites at any time, while the other 
case had a slight rise of temperature two and six days after in- 
oculation, but never showed any parasites. While these four 
cases may be considered as insufficient for final and conclusive 
laboratory evidence on w T hich to reject the theory of partheno- 
genesis, they are of great significance, and together with the 
fact that Schaudinn 's original deductions were based on a single 
case of benign tertian, and that all later evidence brought for- 
ward in support of the theory has been almost universally 
rejected, renders parthenogenetic forms (the very existence of 
which is a matter of great doubt) as being a factor in recurrences 
unlikely. 

Intracorpuscular Conjugation. — The phenomenon of intracor- 
puscular conjugation of the young hyaline parasites was first 
observed by Mannaberg, and later described by Ewing. Neither 



126 MALARIA. 

of these writers attributed to it the significance it deserves : and it 
was Craig who first described in detail the process of development 
and attributed to the resulting bodies the significance of their being 
a factor in recurrences, and he has since amplified the findings 
made in his original report by many additional contributions. 
The writer will not describe in detail this form of the evolution 
of the parasite in man, but will refer those interested to the many 
excellent contributions that the author of this theory has published. 1 
Darling has confirmed the findings of Craig, saying, "the theories 
of Mannaberg and Craig explain the persistence of latent malaria 
by the process of conjugation of two ring forms within a red 
blood corpuscle." He also reports having frequently seen cres- 
centic bodies in latent estivo-autumnal infections which he con- 
sidered had been formed by the conjugation of two ring forms. 
While crescents and the sexual forms of the other types of the 
infection may be formed as a result of this process, we do not 
consider that these bodies have any significance in the etiology 
of recurrences, or that the sexual forms have any other function 
than the perpetuation of the species when transferred to the 
mosquito. 

The author recently had under observation a case of considerable 
significance toward the verification of conjugating bodies. The pa- 
tient had been unwell, complaining of a general malaise for some 
weeks, but showed no clinical symptoms; following routine pro- 
cedure his blood was examined for plasmodia. Several smears 
at intervals covering a period of three weeks failed to reveal the 
parasite in any of its forms, but at the end of this time several 
parasites of a ring form, showing unusually large chromatin masses, 
with the protoplasm also larger than usual and staining an intense 
blue, were observed. The patient had never had malaria previ- 
ously. He was at once put on 30 grains of quinin sulphate per 
diem, but contrary to the usual result, while the fever disap- 
peared, the same organisms were present in the peripheral blood 
for several days and proved very resistant to treatment. The 
author did not observe forms in any advanced stage of de- 
velopment, but is satisfied that what he did see were the result 
of conjugation. Craig has stated that intracorpuscular conjuga- 



1 These have been many, but the author especially calls attention to the very excellent 
monograph published bv Doctor Craig in the Journal of Infectious Diseases, Chicago, 
Vol. VII, No. 2, March 1, 1910, pp. 300-318, entitled "Studies in the Morpholology of 
Malarial Plasmodia after the Administration of Quinin, and in Intracorpuscular Con- 
jugation.' ' 



LATENCY — RECURRENCES — CHRONICITY. 127 

tion never occurs during the first few days of an acute malarial 
infection, and that on this account it is not seen in initial attacks. 
The case referred to would indicate that in persons possessing a 
relative immunity the process may take place even before clinical 
symptoms of the infection are present, and is still another reason 
why we should arrive at a diagnosis of these infections as early as 
possible. 

While the different stages of development up to the form of what 
is considered by Craig to be the presporulating stage have been 
carefully studied by this author, we have as yet no laboratory evi- 
dence that these bodies result in recurrences, and while without 
such evidence it is impossible to absolutely fix their significance, 
we feel confident that they will be proved to be the factor in re- 
lapses of long interval. 

Asexual Reproduction by Schizogony. — It has heretofore been 
thought that the asexual forms disappeared from the peripheral 
circulation in the long intervals between clinical manifestations of 
the infection. Ross and Thomson have shown that this is incorrect, 
and that the error was due to imperfect methods for their detection. 
In conducting some enumerative studies of the disease, by the ap- 
plication of the thick-film method, they show in a series of cases, 
by daily counts, that the asexual forms become less and less after 
an acute clinical manifestation of the disease, sometimes for a 
few days being zero, and from that to four or five per cubic milli- 
meter, but in many of these cases, although for a few days the para- 
sites cannot be detected, they then slowly increase, giving clinical 
evidence of their presence only after reaching some hundreds per 
cubic millimeter. "With this demonstration arises the very im- 
portant question : How long can schizogony continue without giv- 
ing rise to clinical symptoms, and is it a factor in recurrences of 
long interval? 

The almost universal opposition to the acceptance of this theory 
has been that it is unreasonable to infer that schizogony could 
go on for weeks, months, and sometimes for years, sufficiently to 
maintain the infection, but within such limits as to shut out clinical 
symptoms for long periods of time. Ross, who upholds this theory, 
which he says he "will continue to adopt until a better one is 
established," in replying to the argument that it is unreasonable 
to think that the asexual forms can multiply for long periods of 
time, without giving rise to symptoms, but sufficient to maintain 



128 MALARIA. 

the infection, writes: "It is impossible to accept such a train 
of thought. If 150,000,000 sporids cause but a little fever in a 
man of medium weight, 1,000 or 100 should cause none at all, and 
yet will be quite sufficient to keep the infection alive in him. But 
if the parasites are so few, what chance has the medical man of 
finding a single one? If even 1,000 parasites are present in a man 
of 10 st. weight, the chances are that we must search 15,000,000 
hematids before we find one parasite. At the rate of 10,000 hema- 
tids a minute, we shall have to search for 1,500,000 minutes, or 
for twelve hours a day for more than five years, before we suc- 
ceed. " These figures, to say the least, strikingly demonstrate the 
likelihood of negative findings in positive cases. 

It is very evident that there is a factor, at present unknown, 
which is either responsible for the resumed activity of malarial 
Plasmodia in man after periods of latency more or less prolonged, 
or checks activity for these periods. Is it possible that this factor 
is enough to prohibit the multiplication of the parasites to a num- 
ber sufficient to produce clinical symptoms? May it not be the 
same factor, also as yet undetermined, that in untreated cases, by 
the production in the blood of some antitoxic substance, prevents 
the continued multiplication of the parasites to the point that 
would mean death in every instance? 

A review of the literature of the etiology of recurrences, a brief 
resume of which has been given, leads the author to conclude 
that: 

(1) Parthenogenesis cannot be considered a factor in recur- 
rences for the following reasons: 

(a) The very existence of such a phenomenon is a matter of 
great doubt, many observers working over a period of years having 
failed to demonstrate such forms, 

(b) There are many cases reported that have at no time during 
the infection shown the sexual forms, but have frequently relapsed. 

(c) The four cases, cited by Ross, in which inoculation experi- 
ments contained only sexual forms, failed in each instance to 
produce clinical symptoms of malaria, or to reveal the presence of 
any plasmodia ; while in 51 cases cited by the same author inocula- 
tion experiments containing the asexual parasites in every in- 
stance produced clinical symptoms of the infection, and parasites 
of the type inoculated were demonstrated in all of the cases ex- 
perimented with since the discovery of the plasmodia. 



LATENCY RECURRENCES CHRONICITY. 129 

(2) Intracorpuscular conjugation is not an occasional phe- 
nomenon, but is generally present in recurring cases. The ob- 
servations of Craig that certain forms of the plasmodia exist only 
when conjugation is present, and often before gametes have ap- 
peared, would indicate that they are a factor in recurrences of 
long interval, and while they have only been followed by him to 
a presporulating stage, and further observations on their mor- 
phology are necessary to absolutely associate them with recur- 
rences, there is good reason to believe that such studies will 
establish them as the etiological factor in long interval relapses. 

(3) Asexual reproduction by schizogony is generally accepted 
as the cause of short interval relapses, but the length of time that 
the schizont is capable of keeping the infection alive in man with- 
out producing clinical symptoms is at present undetermined, and 
can be only determined by future laboratory observations on an 
extensive scale. 

SIGNIFICANCE OF RECURRING INFECTIONS. 

The significance of a recurring malarial infection is that it is 
prima facie evidence that the original infection did not receive 
appropriate treatment. This results in the patient, not only being 
a sufferer as a result of the infection a longer time than he would 
under proper treatment, but also being a constant menace to the 
community in which he may reside, provided that Anophelines are 
present, which in turn become infected from his blood-stream and 
transmit the disease to others. Just as long as the infection is 
present is there a possibility of the formation of gametes, and as 
already shown, every individual gamete carrier is of considerable 
significance in the perpetuation of the disease. The absence of 
relapsing cases would mean that all first infections w T ere re- 
ceiving proper treatment, the neglect of which at the present time 
is a leading factor in the present endemic index of the disease. 
Craig most truly states that "the practice of regarding such in- 
fections as cured because the active symptoms of the disease have 
disappeared is a most common and a most pernicious one, and one 
that is responsible for the transmission of a very large proportion 
of malarial disease." There is plenty of evidence showing that 
early and efficient treatment arrests the development of gametes, 
and while in exceptional cases conjugating forms, which are prob- 
ably responsible for recurrences of long interval, may form early 



130 MALARIA. 

in the disease, they generally do not form until late in the in- 
fection; so it is evident that, if these cases receive appropriate 
treatment early in the infection, gametes, resulting in the infection 
spreading to non-infected mosquitoes, will not form, and that 
conjugating bodies, which keep the infection latent in man for an 
indefinite period, causing a great deal of suffering, will likewise be 
arrested in development. 

FREQUENCY OF RECURRENCES. 

We think it may be stated that, with the present manner of 
treating malaria in most sections, practically every original in- 
fection is followed by one or more recurrences. It is a somewhat 
hard matter to classify recurrent infections, owing to the fact that 
in a great majority of instances it is practically impossible to ex- 
clude the possibilities of reinfection, in cases that may be suspected 
to be recurrences. Celli considers all cases showing clinical mani- 
festations during the same year as being due to a single infection. 
It is, we think, impossible to accept such a classification, for there 
are undoubtedly many persons infected more than once during 
such a period. The author considers that many such reinfections 
will often be sufficient to precipitate an attack in individuals har- 
boring the parasite in a latent form, which would not at the time 
become active were it not for the added infection, and again slight 
infections might not be sufficient of themselves to precipitate an 
attack, except in those that already harbor a certain number of 
parasites in a latent stage, at the time of this further infection. 
The presence of sexual forms in the blood during the first few 
days of clinical manifestation is evidence that the case is a recur- 
ring one, for these forms do not occur early in an original attack; 
the absence of sexual forms, however, does not prove that the case 
is an original infection, as in some cases none of these forms de- 
velop at any stage of the disease. 

The following tables given by Craig, showing the time of recur- 
rences in the estivo-autumnal tertian and in the benign tertian in- 
fections, are of interest. He states that they are prepared from 
carefully selected cases in which reinfections were extremely im- 
probable : 



LATENCY RECURRENCES CHRONICITY. 



131 



TABLE XIV. 

Recurrences in 55 cases of Tertian Estivo-Autumnal. 



Case 
No. 


Initial 
attack. 


First 
recurrence. 


Second 
recurrence. 


Third 
recurrence. 


Fourth 
recurrence. 


Fifth 
recurrence. 


1 


Oct. 12 
Nov. 19 
Feb. 27 
Nov. 2 
Mar. 30 
Dec. 8 
Jan. 24 
Feb. 12 
Dec. 24 
Feb. 6 
Feb. 6 
Dec. 25 
Mar. 1 
Nov. 29 
Nov. 14 
Feb. 4 
Oct. 30 
Aug. 29 
Mar. 17 
Feb. 4 
Dec. 30 
Jan. 26 
Jan. 11 
Oct, 2 
Nov. 2 
Mar. 2 
Feb. 5 
Dec. 12 
Oct. 29 
Jan. 17 
Jan. 1 
Jan. 19 
Jan. 20 
Oct. 19 
Jan. 19 
Oct. 18 
Jan. 25 
Oct. 21 
Feb. 3 
Aug. 13 
Nov. 27 
Sept. 1 
Oct. 18 
Oct. 17 
Aug. 13 
Sept. 6 
Oct. 31 
Jan. 1 
Nov. 3 
Dec. 7 
Feb. 24 
Oct. 24 
Jan. 18 
June 14 
Mar. 3 


1 days 

' 12 days 

15 days 

18 days 

19 davs 

19 days 

20 days 
20 days 
20 days 
20 days 

20 days 

21 days 

22 days 
22 days 
24 days 
24 days 
24 days 
24 days 

24 days 

25 days 

26 days 
26 days 

26 days 

27 days 
27 days 

27 days 

28 days 

28 days 

29 days 

30 days 
30 days 
30 days 

32 days 

33 days 

34 days 
34 days 
34 days 
36 davs 
36 days 
36 days 

36 days 

37 days 
-38 days 

' 38 days 

38 days 

41 davs 

42 days 

45 days 

46 days 
' 49 days 

50 days 

51 days 
61 days 
64 days 
80 days 


30 days 


36 days 






2 






3 


20 days 
30 days 
20 days 


30 days 
30 days 






4 






5 






6 








7 










8 


60 days 








9 








10 


20 days 
48 days 
33 days 








11 








12 








13 








14 










15 










16 


20 days 
16 days 
26 days 


38 days 


30 days 




17 




18 








19 








20 


16 days 
36 days 
48 .days 
22 days 


20 days 
30 days 
90 days 






21 
22 


90 days 


30 days 


23 






24 








25 










26 


52 days 
21 days 
28 days 
48 days 








27 


20 days 


21 days 




28 




29 


15 days 






30 






31 


30 days 








32 








33 










34 


26 days 
40 days 
50 days 
26 days 
56 days 
66 days 
35 days 


90 days 






35 






36 








37 


17 days 






38 






39 








40 








41 








42 


49 days 








43 








44 










45 










46 










47 


20 days 
30 days 

21 days 








48 








49 








50 








51 


24 days 
39 days 

156 days 
66 days 

120 days 


41 days 






52 






53 








54 

55 


14 days 
96 days 


20 days 


20 days 









132 



MALARIA. 



TABLE XV. 

Recurrences in 18 Cases of Tertian Malarial Infection. 



Case 
No. 



9 
10 
11 

12 
13 
14 
15 
16 
17 
18 



Initial 
attack. 



Nov. 2 

Aug. 4 

Aug. 28 

Nov. 6 

Jan. 17 

Nov. 23 

Oct. 6 

Sept. 17 

Aug. 27 

Feb. 12 

Jan. 17 

July 20 

May 3 

Nov. 1 

Sept. 22 

Sept. 1 

Dec. 13 

Sept. 22 



First 


recurrence. 


16 


days 


18 


days 


19 


days 


20 


days 


20 


days 


21 


days 


21 


days 


21 


days 


22 


days 


22 


days 


27 


days 


30 


days 


30 


days 


30 


days 


33 


days 


37 


days 


38 


days 


41 


days 



Second 
recurrence. 

21 days 

20 days 

30 days 

24 days 

32 days 



20 

30 days 

22 days 

36 days 

18 days 



Third 
recurrence. 



26 days 



30 days 
26 days 



27 days 
16 days 



Fourth 
recurrence. 



46 days 



24 days 



27 days 



Fifth 
recurrence. 



MASKED MALARIA. 

The author has already dwelt on the necessity of ascertaining 
beyond any doubt just what significance should be paid to the 
finding of plasmodia in the blood, in so far as considering to what 
extent they are responsible for existing illness. Whenever they 
are demonstrated in the blood, it is evidence of malarial infection, 
but it need not necessarily mean malarial disease. By this we 
mean : a person presenting himself for examination and treatment, 
complaining of certain clinical evidence of other disease, whose 
blood upon examination shows the presence of plasmodia, who, 
while harboring the parasites, may not necessarily be suffering any 
inconvenience therefrom, is infected with malaria, but the condition 
for which he seeks relief is not malarial disease, and may have no 
bearing whatever on the pathological condition existing. When- 
ever, however, plasmodia are found, it is very necessary that the 
same efficient treatment accorded cases showing clinical symptoms 
be given such cases; but great care should be taken not to allow 
their finding to mask other disease, and it is also imperative that 
other diseases having symptoms in common with malaria should not 
be allowed to mask malarial disease. In cases where quinin has 
been administered before an examination of the blood is made, it 
may often be a hard matter to establish such a diagnosis. The only 
safe rule to adopt, therefore, in all malarial countries, is to be on 
the lookout for coincident malaria in any and all illnesses, and 



LATENCY RECURRENCES CHRONICITY. 133 

the routine examination of the blood of all patients in such dis- 
tricts will often serve to establish a complete diagnosis, thereby 
hastening the convalescence of such individuals. Pulmonary 
tuberculosis, abscess of the liver, dysentery, either specific or amebic, 
typhoid fever, septic conditions, and gonorrhea may be mentioned 
as diseases occurring in malarial districts that frequently mask 
malaria. 

CHRONIC MALARIAL CACHEXIA. 

Individuals suffering from chronic malarial cachexia are seen 
more especially in those sections where the estivo-autumnal infec- 
tions are present. Their clinical picture is one that can hardly be 
overlooked, and while it may be difficult to differentiate the condi- 
tion from such diseases as kala azar, anemias secondary to other 
diseases, such as uncinariasis and chronic sepsis, in fact, any in- 
fection producing degenerative changes in the blood, a careful 
blood examination will clear up the diagnosis. Cases of chronic 
malarial cachexia nearly always present a very much enlarged 
spleen, and there is always marked evidence of anemia, with a 
history of irregular exacerbations of fever. Nephritis is often 
present, and any of the pathological changes that have been de- 
scribed as occurring in the disease may be more or less marked. An 
examination of the blood will reveal a low red-corpuscle count, a 
decrease in the hemoglobin, a leucopenia with marked increase of 
the large mononuclears, diminished eosinophiles, and the presence 
of parasites. The last may not be present in the peripheral 
blood in any great numbers, especially during the period between 
active fever manifestations, but on splenic puncture, or in the deep 
tissues at post mortem, especially the bone marrow, the Plasmodia 
are very numerous. 



CHAPTER VII I. 

PROPHYLAXIS. 

It has been definitely established that the necessary factors for 
the production of malaria are: the presence of malaria-carrying 
mosquitoes, and sexual forms of the parasite in the blood of man. 
With these two factors present, if opportunity is given the mos- 
quito to bite man, malaria will become endemic, more or less, 
depending on the number of mosquitoes present capable of trans- 
mitting the infection, and the number of individuals harboring 
the sexual forms of the plasmodia in their peripheral circulation, 
and only under these conditions can the disease remain endemic. 

The control and prevention of malaria may be considered under 
the following headings : 

(1) Measures directed against the plasmodia. 

(2) Measures directed against the mosquito. 

(3) Mechanical means to prevent the mosquito from gaining 
access to man. 

(4) The education of the public on all measures for the control 
and prevention of the disease. 

MEASURES DIRECTED AGAINST THE PLASMODIA. 

Measures directed against the plasmodia consist of the inter- 
ference with the evolution of the parasite in infected man, by 
medication, for the purpose of preventing the formation of gametes 
and the destruction of those that succeed in forming in the blood. 

It is generally conceded, and has been abundantly demonstrated 
by laboratory observation, that gametes do not form during the 
first few days of an original malarial invasion. We have already 
discussed the formation of gametes in the blood of man, which takes 
place as a result of the action of the human host on the young 
merozoites after sporulation has gone on for some time. On this 
account gametes are not seen in a tertian infection until the disease 
has been dominant for at least a week, while in the quartan and 
estivo-autumnal infections they are not encountered before the 

134 



PROPHYLAXIS. 135 

eleventh day. It is therefore very evident that, if appropriate 
treatment is instituted early, and carried on a sufficient time to in- 
sure the complete eradication of the parasites in all original in- 
fections, the likelihood of gametes ever even forming is practically 
a negative factor ; while, on the other hand, original infections that 
receive improper treatment, or none at all, will develop them in 
a certain percentage of cases. There is also little doubt that a 
new infection responds to treatment much more readily than does 
one that has persisted for some time, and emphasizes the impor- 
tance of an early diagnosis, for, as Celli writes, "the first step 
toward a good and rational prophylaxis is, as usual, the diagnosis 
of the disease, there being other morbid processes which simulate 
the malarial infections." 

With the diagnosis early established, and followed by proper 
treatment being instituted and continued, the chief and most im- 
portant prophylactic measure has been carried out. 

In the preceding chapter Ave discussed the significance of the 
latent malaria carrier. A large proportion of these latent cases 
harbor the sexual forms of the parasite, which renders these in- 
dividuals a menace to the community in which they reside, and it 
is the most serious problem that confronts any locality wishing to 
rid itself of malaria. It is imperative that, in all cases where there 
is reason to suspect malarial infection, an examination for Plas- 
modia in the blood be made, and that in cases where they are found 
vigorous treatment be carried on until such time as repeated ex- 
aminations of the blood show it to be sterile. 

Much stress has been laid, by most writers in the past few years, 
on the necessity for mosquito extermination, but it should be re- 
membered that there are two sources of infection : the mosquito, 
and man. Up to the present time work toward the eradication 
of the disease has been confined almost entirely to the destruction 
of the mosquito, little attention having been given to the other 
source of infection. It is true that a great deal of benefit has been 
secured by the use of screening material, but the use of this prophy- 
lactic unit has been more with the view of preventing mosquitoes 
giving the infection to man than man giving it to the mosquito. 
The presence of gametes, the macrogametes and microgame- 
tocytes, in the circulation of man is a most important etiological 
factor in the perpetuation of the disease, and their presence is the 
result of a process of evolution, and due in the large majority of, 



136 



MALARIA. 



if not in all, cases to improper treatment during and following 
acute clinical manifestations. In many localities mosquito ex- 
termination is impractical on account of the immense fund that 
would be required to rid a community, and to keep it rid, of the 
pest. In such localities, while I do not want in any way to de- 
tract from the valuable work that can be carried on by fighting 
the mosquito to the point of greatest possible reduction, it is very 
necessary that more attention be paid to the destruction of gam- 
etes in man ; for, with this accomplished, myriads of mosquitoes may 
be present, but with their source of infection removed, they are 
rendered harmless, and unable to propagate the species of ma- 
larial organisms, when perforce malaria would disappear.. 

The administration of quinin in doses sufficient to prohibit the 
parasites developing in the circulation of man is an important pro- 
phylactic agent, Celli states, "He who takes quinin every day, 
and therefore has always a supply of quinin in the blood-stream, 
can undergo with impunity inoculations of blood full of malarial 
parasites, and can expose himself with little or no danger to the 
bites of infected mosquitoes." The results obtained in Italy fol- 
lowing the prophylactic use of this drug are shown in the following 
table giving the number of deaths due to malaria from 1900 to 
1907: 

TABLE XVI. 



Year. 


Deaths. 


Year. 


Deaths. 


1900 

1901 


15,865 

13,558 

9,908 

8,517 


1904 

1905 


8,463 

7,845 


1902 


1906. . 


4,871 
4 160 


1903 


1907 . 









There is a difference of opinion among authorities as to the 
requisite dose of the drug necessary for prophylactic purposes and 
as to the best time to administer it. Laveran advocates the admin- 
istration of 0.5 gram every twelfth day, Koch 1 gram every eighth 
day, Ziemann 1 gram every fourth day, and Laborde 0.1 to 0.3 
gram daily. A serious objection to the administration of the drug 
upon given days at fixed periods is that persons are likely to 
neglect taking the drug on the day that it is intended that they 
should, which results in it being taken at irregular intervals, and 
when results are not obtained the efficacy of quinin prophylaxis 



PROPHYLAXIS. 137 

is doubted. It has therefore been my custom to advise the taking 
of five grains of the sulphate of quinin every night upon retiring. 
By adopting this method, regularity is soon acquired, and the taking 
of the drug becomes a fixed habit for the period that is required 
to keep up the use of this prophylactic measure. By following this 
routine very excellent results were obtained by the author among 
a body of soldiers doing field duty in the Philippine Islands. 

While quinin prophylaxis is a very valuable aid in the control 
and prevention of the disease, it should not be relied on to the 
exclusion of other prophylactic measures at our command, but 
when used in conjunction with other methods is of great value. 
It is especially valuable in cases of emergency, when one has to 
be exposed to the bites of Anophelines for short periods of time and 
is without adequate protection by screening or mosquito bars. 
Again, where a person is habitually protected by the latter methods, 
but owing to his occupation is suddenly taken away from such 
protection temporarily and exposed to infection, the use of quinin 
daily, in the dose mentioned, for a period of two weeks following 
such exposure, will often prevent an attack. 

MEASURES DIRECTED AGAINST THE MOSQUITO. 

Measures directed against the mosquito consist of their reduc- 
tion by destruction of the adult insect or their larva?, and may be 
considered under the following sub-headings: (a) physical, (b) 
chemical, and (c) biological means. 

Physical Means. — The destruction of the adult mosquito in the 
home is a practical measure that is easy to put into force under 
any and all circumstances. Even the young children of the house- 
hold can enter into this prophylactic work. Killing mosquitoes in 
the quarters has been given a great deal of attention in the Panama 
Canal Zone, Gorgas laying considerable stress on this prophylactic 
unit. Ross advocates the use of small hand nets, which render 
the capture of the adult insect an easy matter. 

The removal of breeding places (Fig. 25), by drainage and 
filling in, is an important method of ridding a community of ma- 
laria. Where large areas of land have been drained to render 
them suitable for agricultural purposes (Fig. 26), such action has 
in many instances resulted in the complete disappearance of the 
disease where it was previously endemic. In localities situated 
near the coast line, and so situated that drainage is not feasible, 



138 



MALARIA. 



much can be accomplished by digging ditches, allowing the water 
to overflow these low areas at high tide. The author has reported 
the very successful results that were attained by this method, at 
Fort De Soto, Fla., an artillery post on Mullet Key, situated at 
the mouth of Tampa Bay. The mosquitoes at this post were very 
numerous, prevalent to such an extent that military routine and 
all outside work had to be suspended during certain of the warm 
months, but on an expenditure of six hundred dollars, which was 




Fig. 25. — A typical breeding place for anopheles mosquitoes. 

used in digging ditches to the edge of the bay, allowing the water 
to overflow the low areas at high tide, thus destroying the larvae, 
the condition was improved 75 per cent. 

It is not only in the large areas of swamp lands that the Ano- 
phelines breed, for their larva? may be found anywhere where even 
the smallest collections of water are allowed to remain. It is com- 
mon to find them where water has collected in cavities formed in 
decayed trees, in stopped-up gutters and eaves, washtubs, and other 
household utensils around the home, in which water is allowed to 
collect and remain undisturbed for some weeks, so that the motto 
of any community desirous of ridding itself of malaria should be 



PROPHYLAXIS. 



139. 



"no stagnant water." In lowlands where it is not feasible to 
drain, such areas may be filled in, serving the double purpose of 
destroying the breeding places of mosquitoes and reclaiming land 
valuable to the agriculturist. 

The success that follows the destruction of mosquitoes and the 
removal of their breeding places was well shown at Ismalia, a town 
situated on the Suez Canal, with a population of 6,000. Malaria 
had been endemic there for over a hundred years, hundreds of 




Fig. 26. — Large drainage scheme acting in double capacity of removing mosquito breed- 
ing places, and rendering land suitable for agricultural purposes. 

cases occurring annually. In the beginning of 1902, active meas- 
ures against the mosquito were instituted, with the following re- 
sults : 

Year Number of Cases 

1901 1990 

1902 1548 

1903 214 

1904 90 

1905 37 

The place has since been practically free of the disease. 
Equally as good results were obtained at Klang and Port Svvet- 



140 MALARIA. 

tenham, neighboring settlements in the Federated Malay States. 
Active measures to stamp out the disease were commenced in 1902 
with the following results : 

Years ....... 

Cases 



1901 


1902 


1903 


1904 


1905 


510 


199 


69 


32 


23 



During these years the disease increased outside the zone in 
which operations were carried on. 

Ross, in commenting on these operations which consisted mostly 
of drainage, states that most of the cases occurring in Ismalia, 
during the years 1904 and 1905, were cases of relapse among 
patients previously infected, and that the cost of this sanitary meas- 
ure was about a thousand sovereigns ($5,000) per annum for three 
•years, that at Klang and Port Swettenham the cost was about ten 
thousand sovereigns for permanent works, and about four hundred 
sovereigns for annual upkeep. He concludes by saying, "For 
them, as for Ismalia, the medical officers report that malaria has 
practically disappeared. The Health Officer proposing such cam- 
paigns must expect to be put to considerable trouble, but should 
remember that the work is part of his duties. The persistence of 
much malaria in any town can only be looked upon as proof of 
sanitary maladministration." The brilliant results obtained in 
these towns should not be anticipated in every town starting an ac- 
tive campaign against the mosquito, but there is no doubt that 
every dollar judiciously expended' in mosquito eradication will 
prove to be money well spent in any community. It is very neces- 
sary that, with an initial expenditure for the destruction of 
mosquitoes, the work be carried on continuously, and means for 
so doing be provided, as it would oftentimes be a waste of money 
to initiate a campaign for the destruction of mosquitoes, and to 
cease operations at the end of a single season. The length of time 
that active measures have to be carried on will depend entirely 
on the topography and climatic conditions of the country. 

Chemical Means. — A great deal of experimental work has been 
carried on in the past few years, in the hope of finding some prac- 
tical means for destroying larva? found in places that do not allow 
of drainage or filling in. One of the most satisfactory methods 
and one that has accomplished excellent results, in certain sections, 
is the use of kerosene oil, which rapidly spreads over the surface 
of the water, resulting in the death of the wigglers by mechanical 



PROPHYLAXIS. 



141 



means — in coming to the surface for oxygen, they are unable to 
penetrate the oil film, their death resulting. The method should 
only be used in open bodies of water ; ponds, in which weeds, grass, 
etc., are abundant, cannot be successfully treated, as such growth 
interferes with the oil spreading. The method is, however, espe- 
cially valuable in treating small collections of water that cannot 
be drained. Howard was the first to introduce the method in 
1903 ; Le Prince reports the use of a larvicide, consisting of car- 
bolic acid, resin, and caustic soda, with which he has secured sat- 
isfactory results in Panama ; he states that it is very effective, that 
a little of it goes a long way, and that a laborer can carry sufficient 
to carry on work for three or four hours. 

Celli has conducted some extensive experimental work on the 
action of various larvicides; the following table gives the results 
of his observations : 

TABLE XVII. 



Action of Culicidal Substances on the Larvae and Nymphae of 
annulatus). At the Ordinary Temperature (18 


Mosquitoes (C. pipiens, C. 
to 20° O.). 


No. 


Substances used. 


Maximum time required 
to kill. 




Larvae. 


Nymphaa. 


1 




h. m. 

10- 50 
15 
30 

1 15 

2 30 
4 

4 
5 

6 

6 

6 

7 

8 

8 
11 
12 
24 
24 
36 
48 
48 


h. m. 
25 


2 




1 


3 
4 
5 
6 


Salt water (saturated watery sol. NaCl) 

Chrysanthemum powder (unexpanded flowers) 

Chrysanthemum powder (second quality) 

Petroleum c.c. 0.20 in 100 c.m.q. of surface 


1 

1 35 

3 

4 


7 


Potassium permanganate 2% 


4 


8 




6 


9 

10 
11 


Oil (very thin stratum, covering the whole surface of 

the water) 

Petroleum c.c. 0.10 per 100 c.m.q. of surface 


4 
6 

18 


12 
13 


Chrysanthemum powder (unexpanded flowers) 0.0067r 
Formalin (formaldehvde 40%) 


9 
12 


14 


Carburet of lime 10% 


8 


15 
16 


Chrysanthemum powder (second qualitv) 0.06% 

Lysol 0.1 to 0.57c 


12 
24 


17 


Milk of lime 107c 


36 


18 


Commercial chloride of lime 1% 


48 


19 


Commercial chloride of lime 1% 


60 


20 


Potassium bichromate 1% 


60 


21 


Potassium permanganate 17c 


72 









The same author's work on the effect of the aniline dyes is of 
great interest, The writer does not believe that this method has 
been applied in this country, and thinks it is one that should re- 
ceive more attention. Its advantages over the petroleum method 
are best given in Celli 's own words, who writes: 



142 



MALARIA. 



"The aniline dyes in general possess the useful quality of diffusing them- 
selves in an extraordinary way in water, so that a very small amount colors a 
very large quantity of water. Moreover, very weak solutions are sufficient to 
destroy the young larvae rapidly, and if the solution be mfide a little stronger, 
but still very weak, the adult larvae are destroyed in twelve to twenty-four 
hours. Besides, while petroleum, being volatile, evaporates readily, the ani- 
line dyes, on the contrary, remain active for a long time. In a large amount 
of water a solution of one of these two dyes remained active for more than 
two months, killing the larvae in fourteen to twenty hours. The action is 
gradually lost when the water becomes putrid, which, however, in natural 
clear waters, where the larva? of Anopheles develop, does not occur, or occurs 
to a much less extent. 

Consequently these aniline dyes are of great practical value, especially as 
they are not poisonous to man or to mammals, so that the water that contains 
them in solution can be drunk by cattle. 

They are, however, poisonous and deadly to many insects which live in 
marshy waters and cause damage to crops. 

These waters, tinted with aniline colors, are not in the least injurious to 
plants, so that this system of disinfection can also be applied to the water of 
rice fields." 

The three dyes with which he has conducted experiments are the 
green malachite, gallol, and larvicide. 

The following table gives his results with these dyes: 

TABLE XVIII. 

Culicidal Action of Aniline Dyes on the Larvae of Mosquitoes (Gen. Culex.). 









Propor- 




Number. 


Aniline dyes. 


tion per 


Maximum time required 






mille. 


to kill larvae. 








h. h. 






r 


0.50 


6- 12 








0.025 


24- 26 




Green malachite 




0.0125 


34- 48 


1 




0.0062 


36-108 








0.0031 


48- survive 








0.0015 


survive 








0.0007 


survive 






■ 


0.50 

0.025 

0.0125 


6- 12 
16- 24 
24- 36 


2 


Gallol -< 




0.0062 
0.0031 
0.0015 


30- 72 
36- 72 
48-108 






L 


0.0007 


72- survive 






0.50 


2 








0.025 


2, 45 








0.0125 


4 








0.0062 


5 








0.0031 


6 


3 


Larvicide 




0.00125 
0.00062 
0.00031 
0.00015 
0.0007 


7 

9 

16 

24 

48 






- 


0.00031 


72 



PROPHYLAXIS. 143 

The destruction of the adult mosquito by fumigation is an ef- 
fective manner of ridding the home of the insect, While it is the 
natural tendency of the mosquito to leave the habitation of man 
at daylight, houses surrounded by dense foliage may harbor large 
numbers of the insect during the day as well as at night. The 
fumigation method is only practical in instances where a house, 
not adequately screened, is about to be, fumigation being used to 
kill those insects that are already within the dwelling. It is obvi- 
ously absurd to fumigate a residence during the day to rid it of 
mosquitoes, only to have it filled up with others the same night, 
which would of course occur where screening is not in use. As 
mosquitoes will to a certain extent gain entrance in spite of screen- 
ing, fumigation may be employed to kill such as succeed in getting 
in beyond the screens. Various fumigating agents have been used, 
among which may be mentioned, sulphur, tobacco, larvicide, pyre- 
thrum powder, eucalyptus, iodoform, turpentine, camphor, for- 
maldehyde, and ammonia. Boyce advises the use of sulphur, pyre- 
thrum, or camphor and carbolic acid, and gives the following rules 
to be observed in using them : 

Sulphur. — Allow 2 lbs. of sulphur to 1,000 cubic feet. Use two pots, place 
them iu a pan containing' 1 inch of water to prevent damage, and set fire to 
the sulphur by means of spirit. 

Duration. — Three hours. 
Pyrethrum. — Allow 3 lbs. to 1,000 cubic feet, and divide among- two or three 
pots, using the same precautions as with sulphur. 
Duration. — 'Three hours. 
Camphor and Carbolic Acid. — Equal parts camphor and crystallized carbolic 
acid are fused together into a liquid by gentle heat. Vaporize 4 ozs. of 
mixture to each 1.000 cubic feet; this can be done by placing the liquid in a 
wide shallow pan over a spirit or petroleum lamp; white fumes are given off. 
To avoid the mixture burning, the funics should not come in close contact with 
the flame of the lamp. 

Duration. — Two hours. 

Table XIX taken from Celli gives the results of his observa- 
tions following the use of various odors, fumes, and gases, upon 
adult mosquitoes : 

It is hardly necessary to state that before fumigation is com- 
menced with any of these chemicals, all outdoor connections should 
be closed and stopped up in such a manner as to insure the fumes 
of the chemicals being held within the area intended to fumigate. 



144 



MALARIA. 



TABLE XIX. 

Action of Culicidal Substances on Mosquitoes (C. annulatus, C. pipiens, A. claviger) 



No. 



10 
11 

12 

13 

14 

15 

16 
17 

18 

19 
20 



Substances used. 



I. — Odors. 
Odor of essential oil of turpentin( 



iodoform 
menthol 
nutmeg . 
musk . . 



camphor 



leek 

crushed pepper 



naphthalin 

Roman wormwood 



onion 

salvia 

rosemary 

dry and fresh basil 
cinnamon bark 
asafetida 



II. — Fumes. 



Fumes of tobacco 
' ' larvicide 



crysanthemum powder (unexpanded flowers) 
valerian root 



fresh leaves of eucalyptus. . . . 

quassi wood 

pyrethrum powder 

dry leaves of Mentha pulegium . 



pitch 

dry leaves of basil 

dry rosemary , 

culicidal cones 

dry camomile flowers 

dry leaves of Satureja hortensis. 
salvia leaves 



wood 

guaiacum resin 

myrrh 

elemi 

incense 



III. — Gases 



Sulphur dioxid 

Hydrogen sulphid 

Ammonia 

Illuminating gas 

Formaldehyde (Trillat's apparatus) 



Sulphuret of carbon 
Acetylene , 



Time in which death 
is manifested. 



Apparent. 


Actual. 


h. m. 


h. m. 


1 


1 


10 


40 


10 


45 


10 


2 


30 


3 


4- 


4- 


5 


5 


5- 




10 


5 


20 


6 


10- 




35 


8 


6 


24 


4- 




6 


survive 




survive 




survive 




survive 




survive 




survive 




1- 


instantly 


3 


instantly 


5 


5 


1 


5 


2 


3- 




5 


3 


16 


5 


5 


8 


. 5 


8 


10- 




13 


8 


2- 




6 


24 


7- 




12 


24 


2- 




10 


36 


2- 




10 


36 


2- 




10 


36 


8- 




10 


36 


5- 


12- 


7 


48 


12 


survive 


15 


survive 


15 


survive 


15 


survive 


instantly 


1 


instantly 


1 


1 


2 


1 


2 




10- 


2 


15 


15- 




30 


survive 




survive 



PROPHYLAXIS. 145 

Biological Means. — The destruction of larvae by small fish is a 
method by which mosquito reduction can be accomplished. A 
great deal of the success of this method depends on the locality 
and the fish introduced for the purpose ; while many varieties of 
fish will eat the larva?, there are certain ones that devour them more 
rapidly than others. Thus Ross speaks of the small goldfish which 
abound in the ornamental waters of Mauritius, which, he says, 
eat them but not voraciously; on the other hand minnows he saw 
in India would devour a dozen or more in a few seconds. He cites 
the description given by Boyce of the larvicidal propensities of the 
Girardinus pozciloides, popularly known as " millions. " It is 
claimed by Gibbons that the immunity of the Barbadoes from ma- 
laria is due to the presence of these small fish which abound in the 
waters there. There has been but very little work done in the 
way of placing larvae-eating minnows in the waters of America, 
where malaria is prevalent, and it is a matter that should receive 
more serious consideration in the future. It has the advantage 
of being economical, and the expense practically ceases with the 
original outlay, which is not true of most other methods of mosquito 
reduction. 

There are certain other natural enemies of the mosquito larvae. 
Galli-Valerio and De Jongh found that Aspergillus niger and 
glaucus, when introduced into water containing mosquito larvae, 
killed them very rapidly. The larvae of dragon flies are known to 
feed on those of mosquitoes, but their manner of feeding, which 
is on the bottom, makes them of little value in destroying such 
larvae. Ross speaks of M. Rossii, a species of mosquito, which does 
not appear to be able to carry the malarial plasmodia, abounding 
in certain parts of India where malaria is not preA^alent to the 
same extent that it is where this species of mosquito is not found. 
He considers it quite possible that plasmodia-bearing species are 
crowded out by this species, at least to the point below the malaria- 
bearing limit, although not exterminating them entirely. It is an 
interesting fact, which may be mentioned in passing, that De Vogel 
is of the opinion that the ability of the M. Rossii to convey malaria 
depends on whether or not it is bred in salt water. It is, we believe, 
the only species capable of breeding in both fresh and salt water, 
and attempts to incriminate it have been unsuccessful where fresh 
water was the breeding place, while De Vogel working with those 
breeding in salt water succeeded in infecting them. 



146 



MALARIA. 



MECHANICAL MEANS TO PREVENT THE MOSQUITO FROM 
GAINING ACCESS TO MAN. 

Probably the most important action for individual families to 
take, upon moving into a malarial district, is the efficient screening 
of the dwelling. With the mosquito excluded from the home, the 
likelihood of infection is very materially reduced. In fact, where 
the occupation of the members of a family does not necessitate their 
leaving their own dwelling between sundown and sunrise, this 
measure will practically shut out all likelihood of infection. This 




Fig. 27. — A modest dwelling with efficient protection against malarial infection. 

was shown in the case of Doctor Sambon and his associates, who, 
while living in the Roman Campagna, took no other precautions 
against the disease than to retire to their mosquito-proof hut during 
those hours. 

If protection is to be absolute, however, it is very necessary that 
extreme care be taken in the manner of screening, and it must be 
done in such a way as to positively exclude all mosquitoes. Not 
only must doors and windows be suitably screened, but also the 
verandas (Fig. 27). The author has frequently seen 'homes ade- 
quately screened, with the exception of the porches and verandas 



PROPHYLAXIS. 147 

used during the evening hours before retiring, this neglect resulting 
in many infections that probably would not have occurred if this ad- 
ditional precaution had been taken. The selection of screening ma- 
terial is of importance ; the material used should depend entirely on 
the permanency of the protection. Thus, in temporary dwellings or 
in camp life, the ordinary cotton mosquito-netting may be used, 
and will prove very satisfactory, but in dwellings or permanent 
habitations, iron-wire netting, plain or galvanized, or better still, 
a copper-wire netting, should be used. While the last mentioned 
is considerably more expensive, it is probably the cheapest to use 
in the long run, as the life of a screen made with copper netting is 
of much longer duration than when made of other materials. The 
size of the mesh is of more importance than the quality of the 
screening used. Nothing larger than a number sixteen mesh should 
ever be used ; this will exclude practically all mosquitoes, while an 
eighteen mesh is absolutely mosquito proof. The author has always 
advised that the wire screening be tacked upon the window casing, 
and the edges of the wire afterward covered with a narrow strip 
of molding. This does away with the expense of frames, and 
excludes the possibility of defective protection as a result of the 
frame later shrinking, creating an open space between the frame 
and the window. The common custom of using half screens, cov- 
ering only the lower sash, is to be condemned, as it never gives 
permanent effective protection, except in cases where the upper 
sash is nailed in and a permanent fixture. 

If immunity from malaria depends on protection from the 
mosquito, no matter how well the home is screened, the use of a 
mosquito canopy over the bed should not be dispensed with. There 
are so many opportunities for the insect to gain access, such as 
being carried in on clothing, etc., that in spite of all screening at 
least an occasional insect will gain entrance, in districts where 
mosquitoes are very numerous. Their use will be discussed more 
fully later. It is also advisable that all entrances to a dwelling 
be doubly protected against mosquito invasion, by a small vestibule 
having a screened door, in addition to the screened door on the 
entrance proper. Chimneys should be screened on the outside, or 
else the flues, not in use, should be closed by stuffing them with 
paper or other material. 

The confinement of the infected individual, in quarters which 
are properly screened, is a provision that has been very much 



148 MALARIA. 

neglected in even our most modern hospitals. With our present 
knowledge, that mosquitoes can only become infected from infected 
man, it is a matter of wonder that the isolation of the infected pa- 
tient is not more generally observed, but as Craig writes, "Yet 
how seldom we see this precaution taken even in regions in which 
the malarial fevers are endemic and severe. We have seen that 
the mosquito is necessary as an intermediate host in the life history 
of the malarial plasmodia, and that the mosquito becomes infected 
by biting an individual suffering from malarial disease. From this 
it is obvious that, if we can place the infected individual in a po- 
sition where the mosquitoes cannot gain access to him, the trans- 
mission of the infection will be impossible." Malaria should be 
made a reportable disease, and should be classified as a disease dan- 
gerous to the public health. There are at the present time many 
diseases in this classification that are attended with no greater 
danger to the public health than is malaria; and by making it 
compulsory to report and isolate it, much would be accomplished 
toward its prevention and control, and wherever such a law was 
put into effect it would do much toward the eradication of the 
disease. Patients suffering from malaria should therefore be placed 
in wards properly screened, and in private dwellings all such pa- 
tients should be kept under mosquito canopies, at least during the 
hours between sunset and sunrise. 

Wherever the mosquito prevails to such an extent that the dis- 
comforts attendant upon having mosquitoes biting during the 
sleeping hours are marked, the use of mosquito canopies has become 
very general. Too much carelessness is, however, the rule in the 
manner in which these canopies are used, for as a prophylactic 
measure they lose their value, unless proper attention is paid to de- 
tail. There is nothing more dangerous than a fancied protection 
against any disease, which as a matter of fact does not protect, and 
the manner in which the mosquito canopy is very often used is 
a striking illustration of this fact. The many points that have to 
be strictly observed, if all mosquitoes are to be excluded during 
the sleeping hours, may seem of minor importance, but only by their 
strict observance is full benefit derived. Ross has laid down the 
following rules that should be rigidly followed : 

Not a single rent or hole in the net must be allowed. If there is one, mos- 
quitoes, which spend the whole night in exploring every inch of the net in 
the hope of reaching the sleeper, are sure to find it and enter. Not only 



PROPHYLAXIS. 149 

should there be no rent or hole, but the net should be so hung- that no aperture 
for entry is left. Thus it should always be hung inside the poles provided 
for the purpose, and tucked continuously all around the mattress. It should 
not be hung outside the poles, because then it cannot be tucked in .satis- 
factorily in the manner mentioned; and it should not be allowed to hang 
down to the floor unless heavily weighted, because then it is apt to be blown 
up by the wind, thus allowing insects to enter. Moreover, if it is hung down 
to the floor, insects which are hiding under the bed during the daytime will 
often be included. The servant should be instructed to let down the net before 
dark in the evening, and to see that no mosquitoes are inside. If mosquitoes 
do find entry, it is always due merely to carelessness. 

Do not have any opening for the purpose of entering the net. Such openings 
are often used in Europe and allow the insects to go to bed with the sleeper. 
When entering, one should lift the lower edge of the net from the mattress 
as little as possible and slip in with a twisting movement, so as to exclude 
stray mosquitoes, which may have been hovering around outside. If possible, 
use a large bed and a large net in order to avoid the hands, knees, and elbows 
being pushed against the gauze during sleep, and thus being bitten through 
the net by mosquitoes outside. If no large bed and net are available, this 
contingency should be guarded against by sewing a loose valance of gauze 
round the lower part of the net, about 9 inches (23 cm.) above the upper 
surface of the bed, the valance being tucked under the mattress together with 
the net. 

While these directions are all important and should be observed 
in hospital practice, it is not to be expected that such perfection 
will be attained by the laity in any sections. It would be difficult 
to induce housewives generally to observe all of these details, but 
stress should be laid upon the importance of having nets constructed 
so that, when in use, it is impossible for a mosquito to find entry at 
any point, AYe think that a better method than tucking the canopy 
under the mattress is to have one large enough, and properly 
weighted, so that it will hang to the floor free of the bed, and some 
distance from it. Under this method it is impossible for the sleeper 
to unconsciously roll against the netting and be bitten, but if the 
netting hangs against the bed it is much better "to tuck it in all 
around than to run the risk of movement of the bedclothes keeping 
it raised from the floor. 

PUBLIC EDUCATION ON ALL MEASURES FOR THE CON- 
TROL AND PREVENTION OF MALARIA. 

The education of the public on all matters pertaining to the con- 
trol and prevention of malaria is a most important step in a cam- 
paign for its eradication, for without public cooperation it is 



150 MALARIA. 

impossible to secure results. Even in localities where the total 
eradication of the mosquito is feasible, such a measure generally 
calls for the expenditure of public funds, which expenditure will 
only be authorized when public opinion is in sympathy with the 
movement. More important still is it that the public should know 
the entire cycle of the plasmodia in both the mosquito and man; 
the full significance that improperly treated cases have upon the 
entire community; the fact that absence of clinical symptoms, fol- 
lowing a few days of treatment, does not mean a cure of the disease ; 
together with the details of the various prophylactic measures, and 
the necessity for a careful observance of all these entities. 

During the past few years a great deal of work has been carried 
on in teaching the public that malaria is given to man by the 
mosquito, and much benefit has accrued from this educational cam- 
paign. It is now very necessary, and equally important, that the 
laity be also instructed on the fact that man gives malaria to the 
mosquito, that the way in which this is accomplished be explained, 
and that they be taught to fully realize the significant part played 
by man in the perpetuation of the disease. Such an educational 
campaign may be carried on through the columns of the daily press, 
and the articles written in such a manner as to be interesting and 
to attract public attention. A campaign has been recently car- 
ried on in the state of Florida, bulletins being published in all 
of the daily papers of that state, at intervals of a few weeks during 
the course of two summer seasons. The value of a continued and 
systematic educational campaign cannot be overestimated, as will 
be seen by the results obtained in Italy. The combined efforts of 
the Red Cross Society and the Society for the Study of Malaria in 
that country, in which educational work among the peasant classes 
has been a prominent factor, has resulted in a very marked reduc- 
tion of the disease. Passed Assistant Surgeon McLaughlin in a re- 
port to the Surgeon-General of the United States Public Health 
and Marine Hospital Service, in commenting on the prophylactic 
measures taken in that country, writes, "To recapitulate, the war 
against malaria is conducted along these lines: the reclamation of 
marsh land, protection against mosquitoes, obligatory administra- 
tion of quinin, and government control of quinin, insuring a pure 
drug at the lowest possible cost. These energetic measures are 
being carried out with persistence and assiduity. They are bound 



PROPHYLAXIS. 151 

to have, finally, the result hoped for — the extermination of malaria 
as an epidemic disease in Italy." 

In considering prophylaxis in a general way, it should be re- 
membered that measures that will bring about excellent results in 
one section will prove a complete failure in another. AVith our 
present knowledge it should be our aim to educate the public in such 
a manner that its hearty cooperation will be secured, as has been 
done in Italy, and what has been accomplished in that country is well 
pictured by Craig, who writes, ' ' there is probably no one so ignorant 
in that country as to doubt the efficiency of the methods already 
instituted for the suppression of malaria, or who does not know 
why they were instituted, and how they are proving successful." 
With a properly instituted campaign in this country, there is no 
reason to doubt that equally satisfactory conditions could be 
brought about, and the author considers it the duty of every 
physician to work toward such an end ; for the present status of 
malarial infections, and our failure to make any perceptible re- 
duction in them, is not a credit to the medical profession, and re- 
flects discredit on our nation in the sanitary world. 



CHAPTER IX. 
TREATMENT. 

Quinin is so truly a specific in the treatment of the malarial 
fevers that a discussion of treatment of these infections is practi- 
cally limited to : (1) the action of quinin on the parasites, (2) the 
choice of preparation, (3) the time for administering the drug and 
the amount to be administered, and (4) the method of adminis- 
tration. 

HISTORY OF QUININ. 

Mannaberg gives the following history of the introduction of 
quinin, being a translation by Binz from Markham's description: 

In 1638, the Countess of Chinchon, the wife of the Viceroy of Peru, lay very 
ill with tertian fever at Lima, the capital city. The news was carried to 
Canizares, then Corregidor of Loxa, a town among- the Andes in the present 
Ecuador. Though the natives in Peru were unacquainted with the curative 
power of the bark, those of the more northern lying countries appreciated its 
worth, and from them Canizares obtained the secret. He, therefore, sent a 
parcel of it to the vice-queen. Her physician, de Vega, agreed to its employ- 
ment, and she recovered in a short time. In 1640, the Countess returned to 
Spain and carried with her a large quantity of the precious bark, which she 
distributed about her native place in the vicinity of Madrid. De Vega fol- 
lowed and brought likewise a large amount of the bark to Spain, which he 
sold at Seville for a hundred reales a pound. The Countess employed the bark 
so extensively that for a long time it bore the name "Countess' powder" (pulvis 
comitissae ) , and Markham asserts that even today the fame of her deeds in 
that region of Spain continues. The Jesuits, who were the missionaries to 
South America, also did good service in introducing the bark and spreading 
a knowledge of it. 

As we have previously stated, the use of the drug was bitterly 
opposed by certain religious bodies, and it was not until the latter 
part of the seventeenth century that it was generally adopted for 
the relief of malarial disease. The adoption of the drug .was soon 
followed by enormous amounts being administered, but that the 
custom was not universal is testified to by the fact that, while 
Ramazzini wrote that should a fever patient die it was considered 

152 



TREATMENT. 153 

a crime not to have employed cinchona, he and others wrote vehe- 
mently against the abuse of the drug. 

The alkaloid quinin was isolated from the cinchona bark in 1820 
by Pelletier and Caventou, and the various salts of this alkaloid 
have since come into general use. 

For many years, and until recently, it was maintained that the 
action of the quinin salts are only valuable on the asexual forms 
of plasmodia and that their action on the sexual forms is negative, 
but it is now known that all forms of the plasmodia in man can 
be eradicated by the proper administration of the drug. Darling 
was the first to demonstrate that by the continued use of a suf- 
ficient dosage of quinin a sufficient time, all sexual forms are de- 
stroyed, including those of the estivo-autumnal types, and in this 
demonstration has opened up a most important avenue in the 
prophylaxis of the disease. 

ACTION OF QUININ. 

That the administration of quinin in malarial infections cured 
the disease by a direct action on the plasmodia themselves, was 
first assumed by Binz in 1867, and in 1881, Laveran demon- 
strated that the parasites were killed by a 1 : 1000 solution of quinin, 
and stated that "it is because it destroys the parasite that quinin 
causes the disappearance of the manifestations of paludism. ' ' Since 
that time many investigators have studied the effects of the drug 
on the plasmodia, and much confusion has resulted, probably due to 
the staining methods used, many of which were imperfect, and to 
the interpretations arrived at from them. Craig, who in his own 
studies used the modified Wright's stain, which has been already 
described, has had exceptional opportunities in the Philippine Is- 
lands, Cuba, and this country for the study of the plasmodia, 
and has fully described the action of quinin on the different species 
of plasmodia as follows : 

Plasmodium Vivax (Tertian Plasmodium). — The action of quinin upon the 
tertian plasmodium is evident in fresh blood specimens during- every stage of 
the life cycle in man except immediately before sporulation. The changes pro- 
duced by the ding consist chiefly in a granular degeneration of the protoplasm 
and fragmentation, the latter being most common in the nearly full-grown 
parasites. To these changes should be added a great diminution in the amount 
of pigment in the developing forms, thus showing a marked disturbance in the 
nutritive functions of the organisms. 



154 MALARIA. 

The effect of the drug varies with the time of administration and the dose, 
but it is effective upon all but the segmenting bodies, and therefore is curative 
whenever given, whether in one large dose just before sporulation or in 
divided doses. 

If quinin is administered when the young intracorpuscular plasmodia are 
present the changes produced by it are an increase in ameboid motion, followed 
in an hour by a decrease and finally by complete cessation ; an increase in the 
refractive quality of the protoplasm; and finally granular degeneration of this 
portion of the plasmodium. During the stage of stimulation, the ameboid 
motion may become very active, the pseudopodia being projected so swiftly 
that it becomes almost impossible to follow the process. After the cessation 
of motion the young plasmodia become "ring-shaped" or spherical, and much 
more sharply outlined than is the normal tertian, plasmodium. At this stage 
of growth no shrinkage of the organisms was observed as described by Golgi. 

If now the blood be examined at regular intervals, the quinin being con- 
tinued, it will be found that the plasmodia diminished greatly in number up 
to the time of sporulation, proving that at every stage of their growth quinin 
is capable of destroying them. Although this is so, a considerable number 
succeed in developing and finally reproduce by sporulation, but as will be 
shown in studying stained specimens, even these more fortunate organisms 
develop atypically, as the majority of the spores are sterile and incapable of 
further development. 

In those plasmodia which perish prior to sporulation, quinin causes frag- 
mentation, and eventually complete degeneration. Such fragmented parasites 
are very numerous in specimens of blood from tertian infections after the 
administration of quinin, and in those instances in which the drug has been 
given after pigment formation, fragmentation is the most common form of 
degeneration, but is always preceded by increased motility and by an increased 
refractive index. Numerous erythrocytes are observed containing plasmodia 
which are fragmented, the fragments containing pigment in most instances. 
The pigment may be' motile or immotile, and is collected in the form of rather 
large blocks or masses. The protoplasm of the fragmented organism is always 
more refractive than that of the normal tertian plasmodium, and generally 
appears coarsely or finely granular. In many instances the fragmented para- 
sites are extruded in whole or in part from the red blood-corpuscles and thus 
become free in the plasma, from which they quickly disappear, and in tertian 
infections after the administration of quinin it is very common to find many 
free degenerated plasmodia in the blood. Fragmentation of the tertian plasmo- 
dium due to quinin occurs at every stage in the human life cycle of the 
organism up to the sporulating form, but in the latter bodies I have never 
observed any evidence of this process. 

While fragmentation of the plasmodia is very often the result of the action 
of quinin upon these parasites, it does not invariably occur, for many of the 
plasmodia present certain changes which do not eventuate in fragmentation. 
These changes consist in a marked shrinkage in the size of the organism, loss 
of the motility of the pigment, and increase in the refractive index together 
with granular degeneration of the protoplasm. 

Upon the fully developed tertian plasmodium prior to the beginning of 



TREATMENT. 155 

speculation, quinin exerts a marked action, causing a shrinkage of the organ- 
ism, and a markedly granular appearance of the protoplasm, while the pig- 
ment becomes immotile, and is collected in large clumps throughout the pro- 
toplasm or is distributed about the periphery in small masses. Fragmenta- 
tion may occur, but it is not as common as in the younger pigmented forms. 

When quinin is administered just at the beginning of sporulation it pro- 
duces no morphologic changes in the plasmodia, but if it has been present 
during the period of growth of the plasmodia it will be found that the 
sporulating bodies, which have evidently partially resisted the action of the 
drug, are smaller, appear more refractive than normal, while the number of 
spores is reduced. 

There can be no doubt that quinin is very fatal to the young spores result- 
ing from segmentation, while they are yet free in the blood-plasma, but it 
is not fatal to all of them, for in every case careful examination will demon- 
strate that some escape, penetrate the erythrocytes, and undergo more or less 
complete development. This can be demonstrated even in those cases of ter- 
tian malaria which do not present clinical symptoms of the infection, i.e., 
the latent cases. 

From the changes which have been described it is evident that if quinin 
is administered when the blood contains the young intracellular plasmodia of 
tertian malaria it produces death in a certain number, while others are able 
to develop more or less perfectly, but are undoubtedly injured during every 
stage of their growth if the drug be given at regular intervals. This injury 
nun- result in death at a later period of development or by atypical develop- 
ment. If sporulation occurs, the spores are reduced in number, and as will be 
shown in the description of the stained specimens, most of them are sterile. 
Upon all forms of the pigmented tertian plasmodium until the beginning of 
sporulation quinin has a marked action, causing either fragmentation, shrink- 
age in size, or granular degeneration of the organism. The effect of the 
quinin upon all stages of growth of the plasmodium is most marked when it is 
administered in divided doses at regular intervals of time, thus keeping the 
blood supplied with it. If given just prior to the expected chill, in one large 
dose, the majority of the young plasmodia are destroyed while free in the 
blood-plasma, but those which escape and develop present but little evidence 
of the action of the drug, as would be expected, for the blood is free from 
quinin for several hours before the administration of the next close. 

In stained specimens of blood containing the tertian plasmodium the action 
of quinin is very clearly demonstrated. The modification of Wright's method 
already described was used invariably, and invariably the same morphological 
changes were observed after the administration of this drug. From my observa- 
tions I have been able to confirm many of Romanowsky's published results, 
but I have been unable to demonstrate that the chromatin of any of the species 
of plasmodia loses its staining properties, but, rather, I have found that this 
important portion of the nucleus stains even more intensely than normal, 
but that the brilliant red color is replaced by a very dark violet or almost 
black. While this is true, it was invariably observed that the unstained 
portion of the nucleus had disappeared, and in those plasmodia which con- 
tinued the developmental cycle, the chromatin had either failed to divide or 



156 MALARIA. 

divided imperfectly, many of the spores showing no chromatin, as described 
by Mannaberg. The statement of Ziemann that the chromatin remains normal 
in appearance and divides as usual can only be true of those cases in which 
the quinin is administered just before sporulation, for if this drug be given 
during the formation of pigment the vast majority of the plasmodia 
which live to sporulate present either no evidence of division of the chro- 
matin or division is imperfect, only a few of the spores showing any chro- 
matin. 

In order to study the morphologic changes occurring in the tertian plasmodia 
as the result of the administration of quinin it is necessary that the drug 
be given in divided doses to single tertian infections, the first dose just before 
sporulation ; specimens of blood should then be taken at intervals of three 
hours and immediately stained. Given just before sporulation and repeated 
at intervals of every three hours, the quinin acts upon the plasmodia not only 
while free in the plasma, but also upon every stage of their life cycle in 
man, and it is thus possible to study the morphologic changes produced by 
quinin in every stage of the development of these organisms. 

The young, unpigmented "ring forms" stain very intensely after the admin- 
istration of quinin, the protoplasm a much darker blue than normal, while 
the chromatin stains a very dark crimson, often almost black. Besides the 
increase in the intensity of the stain, the loss of the unstained area about 
the chromatin (the vesicular portion of the nucleus) is very noticeable, and 
constitutes a most important evidence of the injurious action of the drug 
upon these parasites. 

In tertian plasmodia a little further advanced in development, the staining 
reactions are the same as for the "ring forms," but the increased motility of 
the plasmodia is shown in the great number and "bizarre" arrangement of the 
pseudopodia. Fragmentation is observed even before the formation of pig- 
ment, some of the unpigmented plasmodia being broken up into deeply stained 
portions, the chromatin lying in one of these portions or free near the periphery 
of the red cell. 

After the formation of pigment, and especially after the plasmodia are from 
one-half to three-quarters grown, the evidence of fragmentation and extrusion 
of the chromatin becomes more marked. Many of the erythrocytes contained 
deep blue portions of protoplasm, the chromatin lying free within the red 
corpuscle. The latter is frequently situated at the extreme periphery of the 
red cell, or even partly outside of it. At this stage numerous extracellular 
plasmodia are observed, either undergoing fragmentation or other forms of 
degeneration. Many of the fragments are entirely devoid of pigment, stain- 
ing a deep uniform blue throughout, while some may be almost filled with 
blocks and granules of pigment. The vesicular portion of the nucleus is 
always absent, nor is there any evidence of an increase in the amount of 
chromatin which is so noticeable in the normal plasmodium when at this stage 
of development. If fragmentation be absent, the protoplasm of the plasmodium 
stains a very dark blue and the chromatin a dark violet or almost black. 
The pigment is generally collected about the periphery of the plasmodium. In 
many instances the chromatin is situated at the extreme periphery of the 
parasite or may lie partly or wholly outside of it within the erythrocyte, 



TREATMENT. 157 

proving that quinin possesses the power of causing extrusion of the chromatin, 
thus rendering the plasmodiurn sterile. 

Together with absence of the vesicular portion of the nucleus there is seldom 
any evidence of increase in the amount of chromatin and of division of the 
latter. 

In fully developed tertian plasmodia fragmentation frequently occurs, many 
of the fragmented parasites being free from chromatin, but the characteristic 
change at this period of development in those plasmodia in which fragmenta- 
tion is absent, as shown by stained specimens, lies in the fact that, although 
the chromatin may be present and stains an intense violet, it has increased 
but little or not at all in amount, and division is either absent or imperfect, 
only two or three small masses being present, which lie close together near the 
periphery of the organism. In tertian plasmodia which have not been acted 
upon by quinin, and have reached this stage of development, the chromatin 
has always greatly increased in amount, and is found divided into numerous 
masses which are scattered throughout the protoplasm. The morphology of 
the plasmodia at this stage of their growth indicates clearly that quinin 
prevents an increase in amount of chromatin and either hinders division or 
prevents it altogether. 

At this stage the protoplasm of the plasmodiurn stains a deep blue and 
the pigment is collected about the periphery in blocks or granules, or more 
rarely distributed throughout the protoplasm in the form of fine granules 
or small clumps. The vesicular portion of the nucleus is always absent. 

Those plasmodia which sporulate after having been exposed to the action 
of quinin throughout their entire cycle of development present very marked 
morphological evidences of the injurious action of the drug, in stained prepa- 
rations. While sporulation may not be entirely prevented, the majority of 
the spores are devoid of chromatin, and are undoubtedly sterile. The spores 
are also greatly decreased in number and may be distorted in shape, while in 
those which show the presence of chromatin the latter is in the form of 
minute irregular masses, very distinct from the compact spherical mass 
observed in normal parasites. Very often sporulating bodies are observed 
in which only two or three of the spores possess chromatin; in such spores 
the protoplasm stains a deep blue, the chromatin almost black, and there is 
no evidence of the vesicular portion of the nucleus. Associated with the 
chromatin containing spores are from six to eight, or perhaps more, deeply 
stained spores devoid of chromatin. In the sporulating plasmodia, the pig- 
ment, instead of being collected in a dense compact mass, as is the rule in the 
normal tertian plasmodiurn, is reduced in amount, and scattered in small 
clumps or granules between the spores. 

From the changes demonstrated in stained specimens of tertian plasmodia 
after the administration of quinin it is evident that this drug*, administered 
in divided doses, exercises a markedly injurious effect upon every stage in 
the human life cycle of this organism, either causing the death of the parasite 
at some period of its development or preventing normal sporulation by re- 
straining the production and division of the chromatin prior to segmentation. 
The death of the organism is evidenced by fragmentation or extrusion of the 
chromatin, while the effect upon sporulation is shown by the lessened produc- 



158 MALARIA. 

tion of this substance, the limited division of the chromatin present, and 
the number of spores which are devoid of this essential portion of the nucleus. 
The loss of the vesicular portion of the nucleus is probably responsible for 
the changes which are observed. 

If quinin is administered in one large dose just prior to segmentation and 
the dose is not repeated, the changes produced are the same in kind as those 
described, but a very large number of the plasmodia escape entirely or are 
but little injured. When given in this way segmentation occurs as usual, 
and both the sporulating bodies and the individual spores appear normal. 

Plasmodium Malariae (the Quartan Plasmodium). — The changes produced 
by quinin in the quartan plasmodium, as shown by, both fresh and stained 
preparations of blood, are practically the same as those described for the 
tertian plasmodium, and I cannot agree with Antolisei and Golgi that upon 
the adult quartan plasmodium quinin has no effect. In the young intracellular 
forms development is hindered or stopped, there being the same initial stim- 
ulation of ameboid movement, while in the older forms fragmentation and 
degeneration occur as frequently as in the tertian plasmodium. I have not 
been able to observe any difference, so far as morphologic evidence goes, in 
the effect of quinin upon the tertian and quartan plasmodia, although it is 
undoubtedly true that because of greater resistance to the drug, a larger 
number of quartan plasmodia escape destruction at the time of sporulation. 
As in the tertian infections, the effect of the drug is most apparent when it 
is administered in divided doses at regular intervals. 

Plasmodium Falciparum. Plasmodium Falciparum Quotidianum (the Ter- 
tian and Quotidian Estivo- Autumnal Plasmodia). — As the effect of quinin is 
the same upon both species of estivo-autumnal plasmodia, I shall consider 
them together. As stated in the historical summary, Marchiafava and Bignami 
found that in fresh specimens, after the administration of quinin, the plasmodia 
assumed a discoid form and left the erythrocytes, while the motility was nor- 
mal or increased. While I have been able to confirm the occurrence of the 
discoid shape, I have not been able to confirm their observations regarding 
the exit of the plasmodia from the red cells. The following observations are 
based upon the study of the action of quinin upon both fresh and stained 
specimens of blood containing the estivo-autumnal plasmodia, including every 
form of the organisms except the fully developed pigmented bodies and the 
sporulating bodies. 

In fresh specimens, a few hours after the administration of quinin in divided 
doses, the time varying with the rate of absorption of the drug, the hyaline 
"ring forms" become much more refractive and sharply cut than normal, while 
the ameboid motion is always greatly stimulated. In most instances, the 
"ring forms," owing to the great increase in the activity of the ameboid 
motion, lose their distinctive form, becoming discoid or assuming irregular 
shapes, and not infrequently change their position in the red corpuscle very 
rapidly, occupying the same portion of the cell only a few seconds at a time, 
but I have never observed their exit from the red corpuscle. 

Upon the larger pigmented forms, and pigmented "rings," quinin appears 
to have less effect, the only change observed in fresh specimens being an in- 
crease in the refractive index, while the outline of the plasmodia becomes more 



TREATMENT. / 159 

sharply defined. I have not observed degeneration by fragmentation in the 
estivo-autumnal plasmodia, although it is so common in the tertian and quar- 
tan parasites. 

In stained specimens the results of my observations are opposed to those 
of Marchafava and Bignami, who claim that no morphologic changes occur in 
these plasmodia after the administration of quinin, and that the unpigmented 
parasites do not become pigmented after its administration. I have repeatedly 
observed pigmented forms of both the tertian and quotidian estivo-autumnal 
plasmodia develop after quinin had been administered for as long as three 
days, while the morphologic changes produced, though not so marked, are 
similar to those observed in the tertian and quartan plasmodia. 

In the "ring forms," which are most easily studied, the staining capacity 
of both the protoplasm and the chromatin is increased, but the unstained area 
surrounding the chromatin disappears. A large number of the "ring forms" 
may appear normal, but careful examination will demonstrate that most of 
them show the loss of the vesicular portion of the nucleus and that the "rings" 
are distorted in shape owing to the increased ameboid motion. In a few 
instances I have observed the separation of the chromatin from the body of 
the plasmodia, thus proving that extrusion had occurred. I have never ob- 
served fragmentation of the "ring forms." 

The changes produced in the young pigmented forms of the estivo-autumnal 
plasmodia, as shown in stained preparations, are similar in every respect to 
those occurring in the tertian and quartan plasmodia, consisting in fragmenta- 
tion, loss of the vesicular portion of the nucleus and extrusion of the chroma- 
tin. . . . 

Upon intracorpuscular conjugation quinin has a fatal influence, for, after 
the administration of this drug, conjugating plasmodia entirely disappear from 
the peripheral blood and do not reappear unless the administration - has been 
stopped, and then only after an interval of days or even weeks. Even in those 
instances in which the drug is given in such small doses as to injure but 
slightly the developing plasmodia, the conjugating organisms quickly dis- 
appear, and as the process of conjugation is undoubtedly intended to assist 
in maintaining malarial infection, the marked action of quinin upon it offers 
another explanation of the efficiency of the drug in curing these fevers if it 
be properly given during the initial attack. 

In 1908-1909, Darling carried on a series of experiments in 
Panama for the purpose of determining the limit of infectiousness 
of man, and the effect of quinin on the number of gametes in the 
peripheral blood. He writes : 

To me this appeared to be, if possible, worth determining, because in the 
discharge of patients from the hospital it would be manifestly unwise to turn 
a patient out, although free from symptoms, yet witli gametes enough in his 
peripheral blood to infect every susceptible anopheles mosquito that might 
bite him. 

His observations established the fact that gametes are eradicated 
from the circulation if quinin is persisted in. He states : 



160 MALARIA. 

The effect of quinin administration on the number of gametes in the 

peripheral blood was studied in a number of patients suffering from estivo- 

autumnal and tertian fever by the administration of 30 grains quinin daily, 

either with or without iron and arsenic, and by withholding quinin and merely 

requiring rest from labor. In estivo-autumnal infections, when there were 

crescents in the blood, the number was reduced by quinin, 30 grains daily, at 

the following rates. For example, in Experiment 17 there were: 

9 crescents per 100 leucocytes on December 26 

5 crescents per 100 leucocytes on December 27 

5 crescents per 100 leucocytes on December 28 

4 crescents per 100 leucocytes on December 30 

1 crescent per 100 leucocytes on December 31 

crescents per 100 leucocytes on January 2 

crescents per 100 leucocytes on January 13 

Other eases showed the following evidence of the action of quinin 
treatment: a case showing 67 gametes per 100 leucocytes was re- 
duced to 1 per 200 leucocytes in 25 days ; another from 92 gametes 
per 100 leucocytes to 1 per 100 leucocytes in 15 days • and one with 
9 gametes per 100 leucocytes was negative in 8 days, while in another 
case in which quinin was withheld, crescents remained constantly 
for 23 days, there being 16 crescents per 100 leucocytes on admis- 
sion, and 20 per 100 leucocytes at the end of the period. He con- 
cludes that: 

Patients having crescents or tertian gametes in their peripheral blood should 
not be discharged from the hospital, nor should treatment be discontinued until 
gametes have been reduced to a non-infectious minimum. The destruction and 
prevention of development of the sexual parasites in man is of great importance 
and may be accomplished : ( 1 ) by appropriate quinin treatment of all gamete- 
carriers entering the hospital; (2) by occasional quinin treatment to destroy 
latent malaria ; ( 3 ) by the periodical examination of laborers in quarters where 
there is a high malarial rate for the detection of gamete-carriers and latent 
malaria in order to carry out appropriate treatment. 

Thirty grains of quinin sulphate in solution daily is an efficient dose for the 
purpose required. 

Bass is of the opinion, in which most authorities concur, that the 
destruction of gametes is not the result of the direct action of 
the drug upon them, but that their eradication is secured by de- 
stroying the schizonts, their source of origin, and that, with these 
removed, the sexual forms in the circulation finally die of old age. 

The effect of quinin on the formation of gametes has been studied 
by Thomson, who reports his observations of a case in which 850 
crescents per cubic millimeter of blood followed a first paroxysm 



TREATMENT. 



161 



accompanied by 50,000 asexual spores per cubic millimeter. 
Twenty grains of quinin were given during this paroxysm, but 
no more was given for several days before or after it. The next 
paroxysm where no quinin was given until the day after produced 
468 crescents per cubic millimeter, and the next only 344 from 
54,000 of the asexual forms per cubic millimeter. At this period 
thirty grains of quinin were given daily, and a later relapse gave 
only four crescents per cubic millimeter, from asexual spores num- 
bering 16,000 per cubic millimeter. 



CHOICE OF PREPARATION OF QUININ. 

While there are several salts of quinin which may be used in the 
treatment of malarial infections, the author has found it necessary to 
employ but a few of them. In the vast majority of cases the drug 
can be administered by mouth, and for this purpose, on account of 
its being cheaper, and in more general use, the sulphate will be 
found to give entire satisfaction. In young children, or in those 
who have difficulty in swallowing capsules, euquinin will be found 
a very useful preparation ; it is very much superior to the tannate, 
a salt that has been popular in treating young children. For 
hypodermatic use the bimuriate of quinin is the one of choice. The 
following table from Manson, with certain modifications by Rosenau 
and Anderson, shows the solubility and equivalent value of the 
various salts of quinin : 

TABLE XX. 

Solubility and Equivalent Value of Salts of Quinin. 



Name of salt. 



Sulphate 

Hyclrochlorid 

Bihydrochlorid (a) 

Hydrobroinid 

Bihydrobroniid 

Bisulphate 

Phosphate 

Valerianate 

Lactate (a) 

Salicylate 

Hydrochloro- sulphate (a) . . . 

Arseniate 

Euquinin 

Tannate 

Bichlorid of quinin and urea 



Percentage 






Amount 


of the 


Solubility in 


sulphate. 


alkaloid in 


cold water. 


of quinin 


the salt. 






value to one 
equivalent in 


73.5 


800 


parts 


1.00 


81.8 


40 


' ' 


.9 


72.0 


1 


" 


1.02 


76.6 


45 


' ' 


.96 


60.0 


7 


' ' 


1.23 


59.1 


11 




1.24 


76.2 


420 


' ' 


.96 


73.0 


110 


' ' 


1.01 


78.2 


10 


' ' 


.94 


70.1 


225 


' ' 


1.05 


74.3 


2 


' ' 


.99 


69.4 


slightly 


soluble 


1.06 


81.8 


slightly 


soluble 


.89 


20.0 


slightly 


soluble 


3.67 


59.2 


1 


part 


1.24 



162 MALARIA. 

TIME AND AMOUNT OF ADMINISTRATION OF QUININ. 

There has been a great deal of discussion as to the best time 
to administer quinin in malarial infections. We have seen that 
the drug has a direct action upon all malarial plasmodia except 
the presegmenting forms, so that it is hardly necessary to discuss 
at length the various theories as to the proper time for the adminis- 
tration of the drug. The three principal methods that have been 
under more or less discussion by modern writers are: (a) Torti's 
method, consisting of a single dose of about fifteen- grains a few 
hours before the expected paroxysm, proceeding on the theory that 
the parasites are more easily destroyed by the drug immediately fol- 
lowing sporulation. A great objection to the single dose lies in the 
fact that in cases presenting other than a typical picture the time 
of sporulation cannot be anticipated with any degree of accuracy. 
(b) Sydenham's method consists of a similar dose given during the 
decline of the paroxysm, and while it is not open to the same 
objection or to an equal degree, it is not always easy in certain cases 
presenting irregular symptoms, especially in mixed or double in- 
fections, to tell just when the stage of decline is upon the patient. 
Another objection to both of these methods is the fact that the 
large single dose is oftentimes not well tolerated by the patient: 
and (c) Manson's method, which consists of the administration of 
ten grains at the commencement of sweating, followed by five grains 
every six or eight hours for the next week, and after that five grains 
three times on one day of the week, or fifteen grains in a single 
dose once a week, for six weeks or two months longer. 

The author has adopted a slight modification of this method, 
giving five grains of the sulphate every four hours during clinical 
manifestations ; after the subsidence of symptoms five grains three 
or four times daily for ten days or two weeks; and after that ten 
grains, in two or three doses, every alternate day for at least a 
month. In those cases seen early in the infection this method will 
generally control the clinical manifestations within forty-eight 
hours. In old recurring infections, however, and especially in the 
estivo-autumnal types showing both asexual and sexual forms, it 
is necessary to use larger doses and for a longer period. In such 
infections, ten grains three times daily should be administered for 
at least three weeks, after which period the dose may be reduced 
to twenty grains per day for an additional two weeks. 



TREATMENT. . 163 

An interesting point has recently suggested itself to the writer. 
He has noticed that in all original cases that have come under 
his observation early in the disease, and in which he was able 
to carry on efficient treatment a proper length of time, not a sin- 
gle reinfection was seen, while reinfections or recurrences, or 
both, are common among those who will not submit to a proper and 
continued treatment. It suggests the important possibility — does 
early and efficient treatment in original infections produce a relative 
immunity to later reinfection? It may be possible that the rapid 
destruction of the young parasites results in the formation of anti- 
bodies that confer an immunity for a certain length of time. 

While the time of administration in benign tertian or quartan 
infections may not be of great importance, Craig is of the opinion 
that "in estivo-autumnal infections quinin should never be ad- 
ministered in one large dose during the twenty-four hours, as such 
treatment invariably results in the febrile condition persisting for 
several days, during which time pernicious symptoms may develop. ' ' 
He states that he has observed "serious results follow the adminis- 
tration of quinin in this manner, some of the patients so treated 
dying from pernicious attacks which might have been controlled 
had the drug been administered in divided doses at regular inter- 
vals." His results in the treatment of estivo-autumnal infections 
with quinin administered in divided doses, in many hundreds of 
cases, have been uniformly satisfactory, and the author has found 
that in nearly every instance the clinical symptoms subside, under 
this method of treatment, within three days, usually within forty- 
eight hours. The author considers, therefore, that the most satis- 
factory method of giving quinin in all malarial infections is in di- 
vided doses at regular intervals. The enormous doses of the drug 
that have been advocated by some, in even recent years, have never 
been found necessary, and it can safely be stated, without fear 
of successful contradiction, that a fever that will not respond to 
thirty grains given within twenty-four hours in divided doses is 
not of malarial origin, or at least is accompanied by some compli- 
cating process. In making such a statement we anticipate that the 
drug is given in such form as to insure its being absorbed. 

METHODS OF ADMINISTRATION OF QUININ. 

Quinin may be given (a) by the mouth, (b) hypodermatically, 
(c) intravenously, or (d) by the rectum. 



164 MALARIA. 

By the Mouth. — In a great majority of cases quinin administered 
by the mouth gives satisfactory results. It may be administered 
in this way in all cases except those developing pernicious symptoms, 
when it becomes necessary to secure more prompt action of the 
drug, or in those cases in which vomiting is a prominent symptom 
during the first few hours of an attack. It is advisable that the 
drug be administered in some form that will eliminate the bitter 
taste, objectionable to most people, and for this purpose the author 
has always found a gelatin capsule the most satisfactory. The use 
of pills and tablets is to be condemned, as they are often more or 
less insoluble, and never liberate the entire dose as rapidly as a 
gelatin capsule. By using a high-grade capsule and prescribing 
with it ten or fifteen drops of dilute hydrochloric acid, well diluted, 
one can be assured that the contained quinin will be freed in the 
stomach and properly absorbed. There are some that advocate the 
administration of the drug in solution, but it is such an unpleasant 
dose to the majority of patients that the author has seldom so used 
it for adults. For children, however, it is his practice to use solu- 
tions entirely, and he has found the syrup of yerba santa, or the 
syrup of orange peel, a satisfactory vehicle. In treating adults it is 
his custom to employ the sulphate almost exclusively, while the 
ethyl-sulpho-carbonate, put on the market under the proprietary 
name of Euquinin, is a most satisfactory salt for employment 
among younger patients, and being tasteless, may be given either 
free in powder form, or combined with any of the aromatic syrups. 
For prophylactic purposes among children the tannate, in the 
form of chocolate lozenges, may be used to advantage. 

Hypodermatically. — Hypodermatic administration of the drug 
is the method of choice in all cases of pernicious malaria, in which 
it is desired to get prompt action of the drug. It will also be 
found of great value when the stomach is very much upset during 
the onset of a paroxysm and rejects anything that is swallowed. 
The author has seen many severe benign tertian infections where 
vomiting was so persistent that administration by the mouth was 
out of the question, which quieted down with a single hypoder- 
matic injection, so that medication by the mouth could be con- 
tinued during the rest of the illness. 

By observing proper precautions the fear of abscess formation 
need not deter one from using quinin hypodermatically ; the quite 
common opinion that abscess is a necessary sequela to its hypoder- 



TREATMENT. • 165 

matic use being an error. A glass syringe with solid-glass piston 
should be employed, and with the needle, should be boiled for at 
least ten minutes. It is the author's practice to wash the site of in- 
jection with soap and water, dry, and paint it with tincture of iodin. 
Instead of placing the solution subcutaneously, the needle should be 
driven well into the muscular tissue ; this method first advocated by 
Koch is less painful and fully as efficient as the subcutaneous 
method. The author has employed, for hypodermatic administra- 
tion, for some years with generally satisfactory results, ampuls con- 
taining 0.30 gram of quinin bihydrochlorid carbamid, which can 
be secured from the Kny-Scherer Co., of New York. The dose em- 
ployed in pernicious cases has been from one to three ampuls in 
adults, while in children the dose is graded according to their age. 
These ampuls will be found a great convenience to the country 
practitioner who may at any time be called upon to administer a 
sterile solution under circumstances that do not favor the home 
preparation of such solutions, and in malarial zones we consider 
no physician's armamentarium complete without a package of these 
ampuls. 

Many solutions have been recommended by various authorities for 
injection purposes, among them may be mentioned the following, 
Kobner recommends : 

Quininae hydrochloridi 5-1 gra. (gr. viij-xv) 

Glyceririi 

Aquae distillatae aa 2 gm. (3 ss) 

Triulzi : 

Quininae hydrochloridi 3 gm. (gr. xlv) 

Antipyrinae 2 gm. (gr. xxx) 

Aquae 6 gm. (3 iss ) 

Deaderick : 

Quininae bihydrochloridi 1 gm. (gr. xv) 

Aqutp 10 gm. ( 3 iiss) 

Intravenously. — Baccelli was the first to use the intravenous 
method, in 1890; he advocated its employment where it was neces- 
sary to get prompt effect, using the following formula : 

Quininae bihydrochloridi 1 gm. (gr. xv) 

Sodii chloridi 0.075 gm. (gr. iss) 

Aquae distillatae 10 gm. (3 iiss) 



166 MALARIA. 

The usual precaution in the preparation of the site of injection 
should be carefully observed; the syringe and needle and solution 
should all be sterilized; and the solution when injected should be 
about body temperature. A tourniquet applied above the elbow 
will render the veins prominent; one well distended is then chosen, 
the needle introduced from below upward, and the entire quantity 
of the solution slowly introduced. The needle is then withdrawn, 
and the site of puncture sealed with iodoform collodion. Baccelli 
claims to have had a greater degree of success with the administra- 
tion of quinin in this manner in pernicious cases than with the 
subcutaneous method, and states that where the mortality in per- 
nicious cases treated by the subcutaneous method was 17 per cent, he 
has reduced it to 6 per cent by using the drug intravenously. 

By the Rectum. — While the administration of quinin by the rec- 
tum has been advocated by many authorities in the past, the method 
is not one that the author would recommend, except possibly in the 
treatment of young children. Absorption takes place very slowly, 
making larger doses of the drug necessary, and such administration 
cannot be continued on account of the local irritation that follows 
its use, so that except in exceptional instances it is not of much 
value. Where it is employed, at least double the amount of the 
drug that would be given by the mouth should be used, the solution 
should be a weak one, with ten drops of tincture of opium added to 
it, and the injection made high up. 

While there are a great many people who will claim that they 
are unable to take quinin, it is seldom that a true idiosyncrasy 
exists, or, if present at all, that it is of sufficient degree to justify 
the discontinuance of the drug. An idiosyncrasy may however ex- 
ist, and in exceptional cases is present to such a degree that even 
the smallest dose of the drug is absolutely prohibited. No attention 
should be paid to the tinnitus aurium, vertigo, or other unpleasant 
symptoms that generally occur in all individuals when the drug is 
used in the necessary dosage ; but when syncope, extreme dyspnea, 
amaurosis, or total deafness occur, it is advisable that the drug be 
withdrawn or at least very cautiously used. 

OTHER METHODS OF TREATMENT. 

While quinin is a true specific in the treatment of all malarial 
infections, it is well to bear in mind other lines of treatment, on 
account of the occasional patients with whom we come in contact 



TREATMENT. - 167 

that really are unable to take it. None of them will compare 
favorably with the specific, but may nevertheless give fairly satis- 
factory results. 

Methylene Blue. — This drug was first advocated by Guttman and 
Ehrlich, in 1891, and its use has been advocated by many others 
since that time. It is, like all substitute treatments, more or less 
unsatisfactory, and the reports from different investigators are 
somewhat at variance. Only the medicinal methylene blue should 
be employed, and it is best administered in three-grain doses four 
or five times during the twenty-four hours. An objection to its 
use is the strangury so commonly followed by its administration ; 
this can be relieved by using a few grains of powdered nutmeg in 
conjunction. 

Thayer reports having seen a case relapse while in bed under 
continued treatment with methylene blue, and while he has seen 
it used with a certain degree of success, writes, "My own experience 
confirms that of most observers that its efficacy is far below that of 
quinin, and uncertain." 

Craig states, ' ' I have used this drug but seldom and have, found 
it unreliable. In rare instances it will effect a cure^ but it is not 
to be compared to the salts of quinin in efficiency. ' ' 

Thomson, who has studied its effect on the crescents, concludes as 
follows : "It would appear from the careful investigation of six 
cases treated with methylene blue alone, that this drug in doses of 
twelve grains daily, given by mouth (pill form), though not so 
potent in destroying the asexual parasites, is yet more potent than 
quinin in preventing crescent formation. It would seem also to 
have some direct destructive effect on the crescents. It is good 
treatment, therefore, to give methylene blue along with quinin, 
especially where one cannot give large doses of the latter due to the 
idiosyncrasy of the patient." 

Deaderick considers that, "it is the best substitute for the deriv- 
atives of Peruvian bark. While it does not compare favorably with 
quinin, requiring a longer time to effect a cure, and failing al- 
together in not a few instances, it seems to possess some specific 
action upon the parasites of malaria, and is the most valuable drug 
where the cinchona preparations are absolutely contraindicated. ' ' 

Picric Acid. — This has been recommended in malaria by many 
writers. Surveyor, who has recently carried on some investigations 
with it, was unable to get any results in a case of benign tertian, 



168 



MALARIA. 



but reports successful results in the treatment of cases with cres- 
cents. His studies comprised 18 cases which had picric acid by 
mouth, 4 cases which had injections of picrate of soda (3 cubic 
centimeters daily of a 4 per cent solution), and as control to the 
picric acid treatment 28 cases which had quinin (with injections in 
six cases), and 6 cases which had quinin together with mercury, 
arsenic, etc. The dose of the picric acid given was 2 grams two or 
three times daily. His method of preparing the solution of picrate 
of soda for injection is as follows: 

Add 4 grams of acid picric to about 75 cubic centimeters of boiling 
distilled water, and to this add, drop by drop, a strong solution 
of sodium hydrate, taking the reaction at the same time, with a 
solution of di-methyl-amido-azo-benzol, until the latter no longer 
turns red. (Do not stop when the dimethyl turns red and subse- 
quently fades, but go on adding the sodium hydrate solution till 
nc change of color occurs.) Confirm with phenolphthalein to see 
that no change of color occurs ; this latter is necessary to ascertain 
whether the solution has become alkaline or not. At this stage, 
most of the picric acid is dissolved. Make up the solution to 100 
cubic centimeters with distilled water; 3 cubic centimeters of this 
solution is put up in test-tubes and sterilized at 120° C. in the 
autoclave. As the water evaporates in these tubes crystals are de- 
posited, which can be readily dissolved either by slightly warming 
the tube or adding a few drops of sterile distilled water. The in- 
jections are no more painful than ordinary injections of vaccine, 
and do not produce any marked reaction, nor is there any nodule 
or swelling noticed at the site of injection. Scarcely any pain is 
present at the end of twenty-four hours, so that there is no dif- 
ficulty in injecting about 3 cubic centimeters of this solution on 
consecutive days. 

The following table showing his results is of interest: 



TABLE XXI. 



Nature of cases. 




Cured. 


Died. 


(No. picric.) Malignant tertian with rings and 


34 

22 


25 (73.53%) 
19 (86.37%) 


9 (26.47%) 


(Picric treatment.) Malignant tertian with 


3 (13.63%) 







He states that the injections of picrate of soda were not found 
to produce any quicker results than the method of administration 



TREATMENT. ' 169 

of picric acid by mouth ; and that it was only employed where the 
patients would not take medicine readily. 

His results, to say the least, justify further experimental work, 
especially in cases that do not stand well the long-continued ad- 
ministration of quinin that is necessary to eradicate the sexual 
forms of the estivo- autumnal infections. 

Treatment with Roentgen Rays. — Schaudinn was the first to 
study the effects of Roentgen rays upon certain protozoa, but his 
efforts were not productive of satisfactory results. More recently 
Skinher and Carson have carried on some work and seem to have 
secured more satisfactory results. They applied the rays in six 
cases, giving an exposure of five minutes, which was followed in 
every instance by a subsidence of clinical symptoms. They do not 
state the type of malaria that was present in these cases, or as to 
whether there was a disappearance of the plasmodia, but state, " Our 
experience has been that the application of x-rays in cases of ma- 
larial fever relieves splenic pain and reduces recent engorgement; 
that the temperature falls and does not usually rise again ; and that 
recovery is not attended by the anemia usually present in cases 
treated with quinin. We have not had to fall back upon quinin in 
cases treated by the x-rays, while we have had cases which resisted 
quinin and yielded promptly to the rays (quinin being discon- 
tinued)." AYhile it may later be proved that this line of treatment 
will secure results, the scope of its usefulness will unfortunately be 
limited, as the necessary paraphernalia will not be obtainable where 
the greatest number of cases occur. 

Other Drugs. — Various other drugs have been mentioned as sub- 
stitutes for quinin, but none of them are worthy of mention. 
Recently salvarsan has been heralded as a panacea for many in- 
fections, including malaria, but the author sees no excuse for the 
administration of a drug which admittedly has an element of dan- 
ger in its administration, when Ave have as comparatively as harm- 
less a specific for the infection as quinin. Sodium cacodylate in 
like manner has its enthusiastic supporters in the treatment of any 
condition suggesting the administration of arsenic, but there is no 
evidence up to the present time that this drug is of any special 
benefit in the treatment of malaria. 

Efforts have been made to secure a serum treatment for malaria, 
Kuhn, Hovorka, and Ford have carried on investigations with this 
end in view, but their results have not been satisfactory. 



170 MALARIA. 

GENERAL MANAGEMENT OF ACUTE MALARIA, AND 
TREATMENT OF SPECIAL SYMPTOMS. 

All patients suffering with acute malaria should be placed in bed 
at least for the period covering acute clinical manifestations, and 
it is advisable that effort be made to keep them in bed for a few 
days after the subsidence of these symptoms, especially in the 
estivo-autumnal infections. A purgative should be administered, it 
being the author 's practice to give five grains of calomel, followed in 
a few hours with a saline. The general management of the case 
should have in view the comfort of the patient, in so far as is con- 
sistent with proper treatment. During the cold stage, heat should 
be employed externally by the use of hot-water bags; while this 
will have no effect on this stage of the paroxysm, it is gratifying 
to the patient. During the period of fever, cool drinks such as 
lemonade may be given, and if the pyrexia is excessive it should be 
combated by baths of tepid or cold water, or sponging with water 
and alcohol. Nothing is to be gained by the administration of 
antipyretics. The old theory, still more or less popular among the 
laity, that quinin should not be given during the height of the 
fever has been discarded, and it is well that quinin be administered 
as early as the diagnosis is established. The disagreeable effects 
following single large doses, which tend to increase the headache 
and general discomfort of the patient, will not be experienced if 
the drug is given in divided doses, as has been already recommended ; 
in fact, the headache will disappear sooner if treatment is promptly 
commenced than it will in untreated cases. The patient should be 
placed on a liquid diet, consisting of the gruels, milk, or broths. 
This diet may be elaborated on as soon as it is evident that the 
attack is under control, and the patient gradually returned to a 
full and nutritious diet. Any special symptoms that develop during 
or following an attack should be met symptomatically. In cases of 
cardiac weakness aromatic spirits of ammonia, strychnin, and 
brandy may be used. If the headache or general pains are espe- 
cially severe they may be controlled by opium ; but the author does 
not favor such treatment except under exceptional circumstances, 
and where it is necessary to use it, codein is the preparation of 
choice. In addition to the treatment by quinin, iron in some form, 
arsenic, and strychnin will hasten convalescence. It is the author's 
practice to use the following formula: 



TREATMENT. 171 

Quininae sulphatis 3 iss 

Ferri reducti 3 ss 

Strychninae sulphatis gr. i 

Arseni trioxidi gr. ss 

Misce et fiant capsular No. xxx. 

The patient is instructed to take one of these capsules three or 
four times a day, and in addition takes what other quinin is neces- 
sary for the complete eradication of the infection, as previously 
discussed in considering the administration of quinin. 

TREATMENT OF MALARIA IN THE PREGNANT WOMAN. 

It may be generally stated that all cases of malaria in pregnant 
women should be treated regardless of this condition. By this, it 
is not meant that care should not be observed in the administration 
of the specific, or that its use is not liable to bring on the expulsion 
of the fetus. The disease if allowed to persist will itself produce 
uterine contractions, and the author is satisfied that pregnant women 
treated for malaria will not abort as frequently as those not treated. 
If possible, a laboratory diagnosis of malaria should be secured, and 
the blood carefully watched during the period of treatment and at 
certain regular intervals following the withdrawal of treatment. 
Quinin should be given only in sufficient doses to control the symp- 
toms, the dose, therefore, depending entirely on the intensity of the 
infection and the degree of resistance of the patient. The author 
has found the following formula of value : 

Quininae sulphatis 3 iiss 

Extracti hyoscyami gr. viiss 

Misce et fiant capsular No. xxx. 

One of these capsules is given every six hours, and the patient 
kept absolutely at rest in bed for several days after the subsidence 
of all symptoms. If uterine contractions become evident, and the 
clinical symptoms of the infection are not severe, the treatment is 
temporarily suspended, to be later renewed. No attempt should 
be made to entirely eradicate the infection during the pregnant 
state, regardless of the manner in which the patient behaves under 
the treatment, but to simply keep the infection under control until 
after delivery, when treatment can be consistently carried on. 



172 MALARIA. 

TREATMENT OF PERNICIOUS FEVERS. 

The treatment of malarial infections developing pernicious symp- 
toms differs, from that in other types, only in the necessity for 
prompt absorption of the specific. On this account the drug should 
always be administered hypodermatically, either intramuscularly or 
intravenously, in the manner already described. The various symp- 
toms that may develop in the various types are treated symptomatic- 
ally. The intense hyperpyrexia should be treated hydrotherapeu- 
tically, or by the application of the ice bag; cardiac weakness with 
stimulants; in choleriform cases the bowels should be controlled 
with opium by mouth, and normal saline solution administered 
by hypodermoclysis ; and in the bilious remittent types the vomiting 
should be controlled by counter-irritation applied over the epigas- 
trium, or the administration of an emetic which will often allay this 
symptom. All cases developing pernicious symptoms should have 
thorough intestinal elimination. The administration of the specific 
will usually control convulsive movements, but in cases that do not 
respond to it, opium or chloral may be administered. Inhalations 
of chloroform will often be found of great service in convulsions, 
especially in the treatment of children. 

TREATMENT OF CHRONIC MALARIAL CACHEXIA. 

Following repeated infections a chronic cachetic state, which is 
very obstinate in responding to treatment, may result. The Plas- 
modia will often be hard to detect, and the only apparent condition 
is one of general anemia usually associated with an enlarged spleen. 
Treatment calls for persistence ; quinin combined with arsenic, iron, 
and strychnin should be employed for prolonged periods. It is in 
this form that arsenic, in the form of Fowler's solution, can be used 
to great advantage ; . the dose should commence with a drop or two 
drops three times a day and be gradually increased to the full 
physiological limit. The solution of iron and acetate of ammonia 
(Basham's mixture) will also be found of service. Craig recom- 
mends the following formula, known as the esanophele pill : 

Quininse bihydrochloridi 0.1 gm (gr. 1-J) 

Arseni trioxidi 0. 001 gm (gr. i^ 4 ) 

Ferri citratis 0.15 gm. (gr. 2^) 

Each pill to contain the above. 



TREATMENT. 173 

Dosage: Children, 3 to 6 years, 

1 pill at 6 A. M. and 1 pill at 6 P. M. 
7 to 14 years, 

2 pills at 6 A. M. and 1 pill at 6 P. M. 
Adults, 

2 pills at 5 A. M., 2 at 8 A. M., and 1 at 6 P. M. 

A change of climate will often do more for these patients than 
many weeks or months of treatment, and on this account, whenever 
their financial condition will permit of such a change, it is advis- 
able to have them go to the mountains or seashore. 

Except where the Plasmodia are active, nothing will be gained 
in these cases by the use of large doses of quinin. It should be the 
aim of the attending physician, however, to keep the blood constantly 
charged with the drug, giving it continuously, and combining with it 
those drugs that are known to have a reconstructive action on the 
blood constituents. The patient should be warmly clad, and well 
nourished, avoid all excesses, and in so far as the conditions will 
allow, lead an outdoor life. 



INDEX OF AUTHORS 



INDEX OF AUTHORS. 



B 



Baccelli, 165, 166 

Banta, 87 

Bass, 29, 34, 73, 108, 160 

Bass and Johns, 34, 73-76 

Bastianelli, 20, 57, 66 

Bell, 105 

Bignami, 20, 57, 66 

Binz, 152, 153 

Bloombergh and Coffin, 82 

Bovce, 143, 145 

Byrd, 122 



Cabot, 31 

Caccini, 66 

Celli, 18, 19, 24, 29, 130, 135, 136, 
141, 144 

Celsus, 18 

Christophers, 67 

Cicero, 18 

Craig, 18, 24, 28, 30, 36, 38, 48, 51, 
52, 54, 57. 64, 66, 69, 80-82, 84, 85 
86, 87, 89, 90, 92, 93, 108. 110, 
111. 122. 124, 126-131, 148, 151. 
153, 159, 163, 167, 172 



Darling. 27. 126, 153, 159. 160 
Deaclerick, 17, 62, 64, 72, 86, 90, 97, 

124, 165, 167 
Delafield and Prudden, 80 
De Vogel, 145 
Dock, 107 



E 



Elting, 125 
Ewino- 103, 125 



Ford, 86, 169 



G 

Galen, 18 

Galli-Vallerio and De Jongh, 145 



Gibbons, 145 

Golgi, 19 

Gorgas, 28, 137 

Grassi, 20, 29, 57 

Grawitz, 80 

Guttman and Ehrlich, 167 

H 

Henson, 105, 109, 138 
Hirsch, 62 
Hippocrates, 17 
Hovorka, 169 
Howard, 25, 131 



James, 105 



K 



Kelsch, 80 

King, 20 

Klebs and Tommasi Crudeli, 19 

Kobner, 149 

Koch, 20, 136, 165 

Krauss, 81 

Kuhn, 169 



Laborde, 136 

Laing, 105 

La Condamine, 18 

Lancasi, 18 

Laveran, 19, 20, 26, 27, 136, 153 

Lavinder, 76 

Leishman, 103 

Le Prince, 52, 141 

Leslie, 24, 64 

Levy, 18 

Liniie, 18 



M 



MacCallum, 20, 26, 29 
McLaughlin, 150 
Mannaberg, 80. 125, 126, 152 
Manson, 20, 21, 23, 26, 27, 70, 91, 
161, 162 



17" 



178 



INDEX OP AUTHORS. 



Marchiafava, 29 

Marchiafava and Celli, 19 

Markham, 136 

Meckel, 18 

Mitchell, 18 

Moore, 86 

Morton, 18 



Nocht, 103 



Osier, 20, 27 



N 







Palmer, 87 

Panse, 69 

Pelletier and Caventou, 153 

Plehn, 70 



R 



Ramazzini, 152 

Ricchi, 25 

Richard, 19 

Romanowsky, 103 

Rosenau and Anderson, 161 

Ross, 20, 21, 26, 27, 29, 32, 48, 66, 72, 

76, 77, 88, 104 124, 125, 127, 128, 

137, 140, 145, 158 



Ross and Thomson, 66, 124, 127 
Ruge, 105 



S 



Salisbury, 18 

Samson, 23 

Schaudinn, 57, 66, 123-125, 169 

Sereni, 66 

Skinner and Carson, 169 

Smith and Kilborne, 20 

Stephens and Christophers, 70 

Surveyor, 167 

Sydenham, 162 



Thayer, 79, 82, 86, 97, 117, 125, 167 
Thomson, 76, 124, 125, 160, 167 
Tommasi Crudeli, 19 
Torti, 17, 18, 162 
Triulzi, 165 
Turck, 70 



Varro, 18 



Wright, 32, 101 



Ziemann, 136 



W 



GENERAL INDEX. 



GENERAL INDEX. 



Abortion, as complication of malaria, 85 

Abscess of the liver, differentiation from malaria, 108 

Acute malaria, 170, 171 

Administration of quinin : 

Henson's method, 162 

hypodermatically, 164 

intravenously, 165 

by the mouth, 164 

for prophvlactic purposes, 136 

rectal, 166 

Sydenham's method, 162 

time of, 163 

Torti's method, 162* 
Age, 64 

Albuminuria in tertian malaria, 114 
Algid tvpe, 118 
Altitude, 62 

Anemia, as a sequela of malaria, 87 
Aniline dyes, as means for destroying larvae, 141 
Anophelines, albimanus, 52 

differentiation, 56 

general description of. 55 

habits of, 52, 53 

migration of, 54 

resting position of, 53 
Aphasic type, 120 
Apoplectic type, 120 

Appendicitis, differentiation from malaria, 109 
Asexual reproduction by schizogony, 127-129 
Aspergillus niger, as means of destruction of larva?, 145 
Asthmatic type, 120 

B 

Bacillus malariae, 19 

Bilious remittent type, 119 

Biological means for destruction of larva 1 , 145 

Blood, 79, 80 

examination, 96 
importance of, 106 

smear, preparation of, 99 
Bone marrow, 83 
Brain, 83 



Cabot's technic for observing exflagellation in human blood, 31 
Cachexia, chronic malarial, 133 

181 



182 



GENERAL INDEX. 



Cardialgic type, 120 

Characteristics of malarial fever, 17 

Chill, stage of, in tertian malaria, 118 

Cholecystitis, mistaken for malaria, 108 

Choleriform type, 119 

Classification of the malarial plasmodia, 28 

Climate, as a predisposing cause, 61 

effect of, on chronic malaria cachexia, 1,73 
on latent malaria, 121 
on parasites, 61 
Clinical diagnosis of malaria, 93-95 

Cinchona, introduced into Europe by Countess Chinchon, 18, 152 
Comatose malaria, 118 
Complications : 

abortion, 85 

dysentery, 84 

gonorrhea, 87 

heart disease, 86 

hookworm disease, 86, 87 

nephritis, 86 

pneumonia, 84 

pregnancy, 85 

syphilis, 87 

tuberculosis, 85 

typhoid fever, 84, 85 
Congenital malaria, 65 
Culex, differentiation of, 56 

resting position of, 53 
Cultivation of malarial plasmodia, 73-76 

Bass' and Johns' technic for, 73 
Cycle, human, 29, 30 

mosquito, 30, 31 



Definition of malarial fever, 17 
Dengue, confused with malaria, 108 
Destruction of mosquitoes: 

biological means, 145 

chemical means, 140-144 

physical means, 137-140 
Diagnosis of malaria, 91-120 

blood examination in, value of, 92 

clinical, 93-95 

differential, 107-112 

errors in, 91 

methods of, 91 

quinin test, 91 
Diaphoretic type, 120 
Diet, effect of improper, 64 
Differential diagnosis of malaria, 107-112 
Differentiation of malaria from abscess of the liver, 108 

from appendicitis, 109 

from cholecystitis, 108 

from dengue, 108 

from dysentery, 110 

from kala azar, 110 

from septic infections, 110, 111 

from sunstroke, 110 

from tuberculosis, 109 



GENERAL INDEX. 

Differentiation of malaria — Continued 

from typhoid fever, 107, 108 

from yellow fever, 109 
Distribution of malaria, 21-24 

in Africa, 23 

in Asia, 23 

in Australia, 23 

in Europe, 23 

in North America, 22 

in South America, 21 

in West Indies, 22 
Distribution of malaria-carrying mosquitoes, 51 
Ditches, as means of extermination of mosquitoes, 138 
Drainage, as means of extermination of mosquitoes, 137 
Dysentery, as complication of malaria, 84 

differentiation from malaria, 110 

E 

Eclamptic type, 118 
Economic loss, 24, 25 

in Italy, 24 

in India, 24 

in the United States, 25 
Fducation and prophylaxis, 149, 150 
Endemic index, 70-72 
Equivalent value of quinin, 161 
Fsanophele pill, 172 
Estivo-autumnal Plasmodium, 28 
Estivo-autumnal infections, 114-116 

microoametocytes in, 50 

quotidian form, 116 

sexual forms in, 48 

tertian form, 114, 115 
Etiology, 51-78 
Euquinin, 164 

Evolution, forms of, in man and mosquito, 28 
Examination of blood, 96 

importance of, 106 
Exflagellation, Cabot's technic for observing in human blood, 31 



Fever in tertian malaria, 112, 113 

Fish, as means of destruction of larvae, 145 

Flagella, 31 

Food in etiology, 64 

Freomency of different infections, 111 

of recurrences, 130-132 
Fumigation method of destruction of mosquitoes, 143 



183 



G 



Gametes, crescentic formations of, 48 
description of, 46-50 
destruction of, importance of, 136 
differentiation of younger forms, 47 
macrogametes, 30 
microgamete, 30 
microgametocytes, 30 



184 



GENERAL INDEX. 



Gametes — Continued 

nutrient vacuole in, 47 

Schaudinn theory of formation of, 30 

schizont of benign tertian infection, 48 

staining qualities, 46-50 

Wright's stain in, 50 
Gastric type, 120 

Glaucus, as means of destruction of larvae, 145 
Gonorrhea, as complication of malaria, 87 



Heart disease, as complication of malaria, 86 

Hemosiderin, 79 

Henson's method of administration of quinin, 55 

modification of Ross' technic, 105 
Hibernation of mosquito, 55 
History of malaria, 17 

in the Middle Ages, 18 

in Panama, 21 

in the Roman Empire, 18 
Hookworm disease, as complication in malaria, 86 
Human cycle, 29, 30 
Hypodermatic administration of quinin, 164, 165 

I 
Idiosyncrasy, 166, 167 
Incubation, period of, 66, 67 

Indifference displayed towards the infection, 27 
Insect transmission, theory of, 20 
Intense infections, factor in, 67, 68 
Intestinal tract, 83 

Intracorpuscular conjugation, 125-127, 129 
Intravenous administration of quinin, 165 
Immunity to malarial infections, 68, 69, 70 



James' modification of Ross' technic, 105 

K 

Kala azar, differentiation from malaria, 110 
Kerosene oil, as means for destroying larvae, 40 
Kidneys, 83 



Laboratory diagnosis of malaria, 96-107 

microscope, use of in, 96 
Larvae, means for destruction of, 137 

aniline dyes, 142 

fish, 145 

kerosene oil, 140 

larvicides, 141 
Larvicides, as means of destroying larvae, 141 
Latent malaria, 121-123 
Leishman stain, 103 
Leucocvtes, 80, 81 
Liver, 82. 83 



GENERAL li\DEX. 185 

M 

Macrogametes, 30, 46-50 

characteristics of. 49 
protoplasmic stains in, 49 
Malaria: 
acute, 170 
altitude, 62 

amount of, in given community, factors in determining, 76-78 
bone marrow in, 83 
brain in, 83 
climate, 61 
complications, 84-87 

abortion, 85 

dysentery, 84 

gonorrhea, 87 

heart disease, 86 

hookworm disease, 86, 87 

nephritis, 86 

pneumonia, 84 

pregnancy, 85 

syphilis, 87 

tuberculosis, 85 

typhoid fever, 84, 85 
congenital, 65 
cultivation of plasmodia, 73 

technic for, 73 
definition of, 17 

development of plasmodium in the mosquito, 56, 57 
diagnosis, 91-120 

clinical, 93 

differential, 107 

estivo-autumnal infections, 114 

laboratory, 96 

pernicious fevers, 116 

symptomatology, 112 
distribution of, 21-24 
effect of civilization on, 26 

of residence on, 65 
endemic index in, 70 
etiology of, 51-78 

factor in intense infections, 67, 68 
history of, 17 
immunity to, 68 
improper diet in, 64 
indifference displayed towards, 27 
intestinal tract in, 83 
kidnevs in, 83 
latent, 121-123 
liver in, 82, 83 
masked, 132, 133 
mortality from, 27, 28 
named by Torti, 17 
occupation, 63 

old-time theories concerning transmission, 72 
pathogenesis of, 66 
pathology of, 79-84 
period of incubation, 66 
pernicious. 116-120 
predisposing factors of, 61 



186 



GENERAL INDEX. 



Malaria — Continued 

prevalence in tropical and subtropical countries, 26 
produced by specific organisms, 26 
prognosis, 88-90 
prophylaxis, 134-151 

measures directed against the plasmodia, 134-137 
measures directed against the mosquito, 137-149 
biological means, 145 
mechanical means, 146-149 
physical means, 137-144 
public education for control and prevention, 149-151 
quartan, 30, 114 
quinin, first used in, 18 
quotidian, 31 
race, 63 
rainfall, 62 

recurrences, etiology of, 123 
in Roman Empire, 18 
season, 62 
sequelae, 87, 88 
in the blood, 87 
in the genitourinary system, 87 
in the glandular system, 87 
sex and age, 64 
spleen in, 81, 82 
•surgical operations in, 65 
tertian, 32, 112 
treatment, 152-173 
methylene blue, 167 
picric acid, 167 
quinin, action of, 153 
administration of, 162 
preparation, choice of, 161 
history of, 152 
Roentgen rays, 169 
serum, 169 
salvarsan, 169 
Malaria-carrying mosquitoes, 51-60 
distribution of, 51 
list of, 51 
Malarial index in Florida, 123 
Malarial plasmodia, classification of, 28 

description of, 32 
Manson's method of administering quinin, 162 
Masked malaria, 132, 133 
Measures directed against the mosquito, 137-146 

Plasmodia, 134-137 
Melanin, 79 
Merozoite, 29 
Methylene blue, 167 
Microgametes, 30, 46-50, 57-60 
Microgametocytes, 30, 46-50, 57-60 

staining in, 50 
Microscopic examination of blood, 96-107 
Minnows, as means of destruction of larvae, 145 
Mortality of malaria, 27, 28 
among negro children, 64 
statistics of, 89, 90 
Mosquito, cycle of, 30, 31 

destruction of, biological means of, 145 



GENEKAL INDEX. 

Mosquito, destruction of — Continued 
chemical means of, 140 
physical means of, 137 
development of malarial plasmodium in, 57 
exflagellation in stomach of, 32 

extermination of, impractical in many localities, 136 
forms of evolution, 28 
liberation of, 55 

malaria-carrying, distribution of. 51 
list of, 51 
Mouth administration of quinin, 164 

N 

Nephritis, as a complication of malaria, 86 

as a sequela of malaria, 87 
Nocht stain, 103 

O 

Occupation as a predisposing factor, 63 
Oocyst, 31 
Ookinete, 31 



Parasites, in the blood, discovered by Laveran, 19 

classification of, 28-30 

determination of species, 42, 43 

effect of quinin on, 153 
Parthenogenesis, 123-125 
Pathogenesis, 66 
Pathology, 79-84 
Pernicious fevers, 116-120 

algid type, 118 

aphasic type, 120 

apoplectic type, 120 

asthmatic type, 120 

bilious remittent type, 119 

cardialsric type. 120 

choleriform type, 119 

comatose type, 118 

diaphoretic type, 120 

eclamptic type, 118 

gastric type, 120 

hemiplegfic type, 120 

pneumonic type, 119 

rheumatic type, 120 

tetanic type. 120 

treatment of, 172 

typhoidal type, 120 
Perspiration in tertian malaria, 113 
Petroleum, as means for destruction of larvae. 40 

Physical means for destruction of adult mosquitoes or larva?, 137-140 
Picric acid, 167 

method of preparation, 168 
Plasmodia in the blood, as positive evidence of malarial infection. Ill 
Plasmodium falciparum, 39, 40 

cycle of. 39 

sporulation, 40 



187 



188 



GENEKAL INDEX. 



Plasmodium falciparum quotidianum, 40-42 

cycle, 40 

differentiation, 41 

distribution, 40 

sporulation, 41 
Plasmodium malaria?: 

cycle, 36 

changes in blood, 38 

differentiation, 36, 37 

falciparum, 28 

falciparum quotidianum, 28 

vivax, 28 
Plasmodium vivax, 32-36 

action of quinin on, 153 

Bass' and Johns' experiments in Panama, 34 

differentiation, 35 

human cvcle, 32, 33 

Schuffner's dots, 36 

sporulation, 33 
Pneumonia, as complication of malaria, 84 
Pneumonic type, 119 

Pregnancy, as complication of malaria, 85 
Pregnant woman, treatment of malaria in, 171 
Premature labor, as complication of malaria, 85 
Preparation of quinin, choice of, 161 
Prognosis, 88-90 
Prophylaxis, 134-151 
Pyelitis, mistaken for malaria, 111 

Q 

Quartan malaria, 30 (see also Plasmodium malariae) 

symptoms of, 114 
Quartan malarial plasmodium, 28 
Quinin : 

action of, on gametes, 159-161 

on intracorpuscular conjugation, 159 
on plasmodium falciparum, 158 
on plasmodium falciparum Quotidianum, 158 
on plasmodium malarise, 158 
on plasmodium vivax, 153 
administration of, 162-166 
first used in malaria, 18 
history of, 18, 152 
preparation, choice of, 161 
prophvlaxis, 136, 137 
solubility of, 161 
test, for diagnosis of malaria, 91 
Quotidian estivo-autumnal malaria, 40-42 (see also Plasmodium falciparum 

quotidianum) 
Quotidian estivo-autumnal plasmodium, 28 
Quotidian malaria, 30 

R 

Race, 63 
Rainfall, 62 

Rectal administration of quinin, 166 
Recurrences, asexual reproduction, 127-129 
etiology of, 123-129 



GENERAL INDEX. 189 



Recurrences — Con tinned 

frequency of, 130, 132 

intracorpuscular conjugation, 125-127 

parthenogenesis, 123-125 

significance of, 129, 130 
Residence, effect of, 65 
Rheumatic type, 120 
Roentgen rays, treatment with, 169 
Roman Empire, effect of malaria on, 11! 
Romanowsky stain, 103 



Salvarsan, 169 

Schizogony, 29 

Schizont, 29 

Schuffner's dots, 36 

Screens, 146-149 

Seasons, effect of, on malaria, 62, 122 

Septic infections, differentiation from malaria, 110, 111 

Sequela? of malaria, 87, 88 

anemia, 87 

nephritis, 87 

splenomegalia, 87 
Serum treatment, 169 
Sex, 64 

Significance of recurring infections, 129, 130 
Social conditions, 122 

Soil, disturbance of, as etiological factor, 73 
Solubility of quinin, 162 

Solutions of quinin for injection purposes, 165 
Spleen, 81, 82, 114 
Spleen rate, 70, 72 

Splenomegalia as a sequela of malaria, 87 
Spores existing in marshes as etiological factor, 18 
Sporogony, 29, 31 
Sporozoites, 29, 32 
Staining reactions of the estivo-autumnal parasites, 45 

of the microgametocyte, 47 

of the plasmodia, 42-46 

of the quartan parasite, 45 

of the tertian parasite, 42-45 
Sunstroke, differentiation from malaria, 110 
Surgical operations, 65 
Swamps, 138 

Sydenham's method of administering quinin, 162 
Symptoms, special treatment of, 172 
Symptomatology, 112-114 
Syphilis, as complication of malaria, 87 



Technic for cultivation of plasmodia from blood, 73 

Tertian estivo-autumnal malaria, 39, 40 {see also Plasmodium falciparum) 

table showing recurrences in, 131 
Tertian malaria, 32-36 {see also Plasmodium vivax) 

symptoms of, 112-114 

table showing recurrences in, 132 
Tertian malarial plasmodium, 28 
Tetanic type, 120 



190 GENEEAE INDEX. 

Theories concerning transmission, old-time, 72, 73 
Thick-film method in preparation of blood smear, 104 
Ross' original technic, 105 
James' modification, 105 
Henson's modification, 105 
Thin-film method in preparation of blood smear, 100 
Time of administration of quinin, 163 
Torti's method of administration of quinin, 162 
Treatment : 

of malaria, 152-173 

with quinin, action of, 153 

administration of, time and amount, 162 

methods of, 164 
history of, 152 

preparation of, choice of, 161 
with Roentgen rays, 169 
of acute malaria, 170 
of chronic malarial cachexia, 172 
of pernicious fevers, 172 
of pregnant women, 171 
of special symptoms, 170 
Trophozoites, 29 
Tuberculosis, as complication of malaria, 85 

differentiation from malaria, 109 
"Typho-malarial fever," 85, 107 
Typhoid fever, as complication of malaria, 84, 85 

differentiation from malaria, 107 
Typhoidal type, 120 

U 

Ulcerative endocarditis, mistaken for malaria, 111 
Uncinariasis, as complication of malaria, 86 

W 

"Wright's Blood Stain," 102 

Wright's modification of the Leishman stain, 101, 102 



Yellow fever, elimination of, compared with malaria, 28 
differentiation from malaria, 109 



Zygote, 32 



AUG 20 1913 



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